Stat degraders and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/736,669, filed May 4, 2022, which is a division of U.S. patentapplication Ser. No. 16/841,095, filed Apr. 6, 2020, which claims thebenefit of U.S. Provisional Application No. 62/830,095, filed on Apr. 5,2019, U.S. Provisional Application No. 62/833,331, filed Apr. 12, 2019,U.S. Provisional Application No. 62/855,259, filed May 31, 2019, U.S.Provisional Application No. 62/860,512, filed Jun. 12, 2019, U.S.Provisional Application No. 62/875,362, filed Jul. 17, 2019, U.S.Provisional Application No. 62/877,051, filed Jul. 22, 2019, U.S.Provisional Application No. 62/887,872, filed Aug. 16, 2019, U.S.Provisional Application No. 62/926,127, filed Oct. 25, 2019, U.S.Provisional Application No. 62/932,957, filed Nov. 8, 2019, U.S.Provisional Application No. 62/944,810, filed Dec. 6, 2019, U.S.Provisional Application No. 62/947,310, filed Dec. 12 2019, U.S.Provisional Application No. 62/949,053, filed Dec. 17, 2019, and U.S.Provisional Application No. 62/967,921, filed Jan. 30, 2020, the contentof each of which is hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for themodulation of one or more signal transducers and activators oftranscription (“STAT”) via ubiquitination and/or degradation bycompounds according to the present invention. The invention alsoprovides pharmaceutically acceptable compositions comprising compoundsof the present invention and methods of using said compositions in thetreatment of various disorders.

BACKGROUND OF THE INVENTION

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulateskey regulator proteins and degrades misfolded or abnormal proteins. UPPis central to multiple cellular processes, and if defective orimbalanced, it leads to pathogenesis of a variety of diseases. Thecovalent attachment of ubiquitin to specific protein substrates isachieved through the action of E3 ubiquitin ligases.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487)titled “Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates theorganelle's dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol.Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligasemechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434)titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures,new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014,14, 233-347) titled “Roles of F-box proteins in cancer.”

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. The pathway has been implicatedin several forms of malignancy, in the pathogenesis of several geneticdiseases (including cystic fibrosis, Angelman's syndrome, and Liddlesyndrome), in immune surveillance/viral pathogenesis, and in thepathology of muscle wasting. Many diseases are associated with anabnormal UPP and negatively affect cell cycle and division, the cellularresponse to stress and to extracellular modulators, morphogenesis ofneuronal networks, modulation of cell surface receptors, ion channels,the secretory pathway, DNA repair and biogenesis of organelles.

Aberrations in the process have recently been implicated in thepathogenesis of several diseases, both inherited and acquired. Thesediseases fall into two major groups: (a) those that result from loss offunction with the resultant stabilization of certain proteins, and (b)those that result from gain of function, i.e. abnormal or accelerateddegradation of the protein target.

The UPP is used to induce selective protein degradation, including useof fusion proteins to artificially ubiquitinate target proteins andsynthetic small-molecule probes to induce proteasome-dependentdegradation. Bifunctional compounds composed of a target protein-bindingligand and an E3 ubiquitin ligase ligand, induced proteasome-mediateddegradation of selected proteins via their recruitment to E3 ubiquitinligase and subsequent ubiquitination. These drug-like molecules offerthe possibility of temporal control over protein expression. Suchcompounds are capable of inducing the inactivation of a protein ofinterest upon addition to cells or administration to an animal or human,and could be useful as biochemical reagents and lead to a new paradigmfor the treatment of diseases by removing pathogenic or oncogenicproteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; SchnneklothJ S Jr., Chembiochem, 2005, 6(1):40-46).

An ongoing need exists in the art for effective treatments for disease,especially hyperplasia and cancer, such as breast cancer. However,non-specific effects, and the inability to target and modulate certainclasses of proteins altogether, such as transcription factors, remain asobstacles to the development of effective anti-cancer agents. As such,small molecule therapeutic agents that leverage E3 ligase mediatedprotein degradation to target cancer-associated proteins such as signaltransducers and activators of transcription (“STAT”) hold promise astherapeutic agents. Accordingly, there remains a need to find compoundsthat are STAT degraders useful as therapeutic agents.

SUMMARY OF THE INVENTION

The present application relates novel bifunctional compounds, whichfunction to recruit STAT proteins to E3 ubiquitin ligase fordegradation, and methods of preparation and uses thereof. In particular,the present disclosure provides bifunctional compounds, which findutility as modulators of targeted ubiquitination of STAT proteins, whichare then degraded and/or otherwise inhibited by the bifunctionalcompounds as described herein. Also provided are monovalent compounds,which find utility as inducers of targeted ubiquitination of STATproteins, which are then degraded and/or otherwise inhibited by themonovalent compounds as described herein. An advantage of the compoundsprovided herein is that a broad range of pharmacological activities ispossible, consistent with the degradation/inhibition of STAT proteins.In addition, the description provides methods of using an effectiveamount of the compounds as described herein for the treatment oramelioration of a disease condition, such as cancer, e.g., breastcancer.

The present application further relates to targeted degradation of STATproteins through the use of bifunctional molecules, includingbifunctional molecules that link a cereblon-binding moiety to a ligandthat binds STAT proteins.

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asdegraders of STAT proteins. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

It has also now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asdegraders of STAT proteins. Such compounds have the general formula II:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating STAT proteins. Such diseases, disorders, orconditions include those described herein.

Compounds provided by this invention are also useful for the study ofSTAT proteins in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in bodily tissues;and the comparative evaluation of new STAT inhibitors or STAT degradersor other regulators of cell cycling, metastasis, angiogenesis, andimmune cell evasion, in vitro or in vivo.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the binding IC₅₀ (μM) of I-1 to both STAT3 and E3 ligase.

FIG. 2 includes images of the results of an AlphaLISA assay (A) and A549lysates (B) of I-1 indicating efficient ternary complex formation andSTAT3 ubiquitination.

FIG. 3 includes graphical images showing the results of an endogenousSTAT3-HiBiT live cell assay in A549 (A) with HiBiT signal (%control)(y-axis) over I-103 concentration (nM)(x-axis) at 0.5, 1, 2, 4,6, 8, 24, and 48 hours and a MSD assay of STAT3 levels in heme cellslines MOLM-16 and SU-DHL-1 at 24 hours (B) with STAT3 protein (%control)(Y-axis) over I-103 concentration (nM)(x-axis).

FIG. 4 includes images of deep tandem mass tag (TMT) proteomicscatterplots in MOLM-16 (AML) and SU-DHL-1 (ALCL) at 8 hours showing−Log 10 p-value (y-axis) and Log 2 fold change at 30 nM and 100 nM I-103in DMSO (x-axis).

FIG. 5 . Includes graphical images and tables showing the results ofRT-qPCR in SU-DHL-1 cells at 24 hours (A) with mRNA levels (% control)over I-103 concentration (nM)(x-axis) for STAT3, SOCS3, and PDL-1 genesand CellTiterGlo (CTG) cell viability at 4 days (B) with growthinhibition (% control) over I-103 concentration (nM)(x-axis) for MOLM-16and SU-DHL-1 cell lines. Also shown are the results of MSD degradationDC₅₀ (nM) in MOLM-16 and SU-DHL-1 cell lines at 24 hours.

FIG. 6 includes graphical images of MOLM-16 and SU-DHL-1 tumor xenographresults using I-103 for STAT3 and pSTAST3 degradation (A), efficacy inNOD/SCID mice (B) with tumor volume median (mm³) over days (postrandomization) for vehicle, 25 mg/kg IP QD, and 50 and 100 mg/kg SC BIWdosing, STAT3 and pSTAT3 degradation (C) with STAT3, and pSTAT3(relative STAT3/Actin)(left y-axis) and plasma concentration (μM)(righty-axis) for vehicle, 25 mpk QD×2 (24 hours post dose), and 50 mpk QD×1(48 hours post dose), efficacy in NOD/SCID mice (D) with tumor volumemedian (mm³) over days (post randomization) for vehicle, 25 mg/kg IP (2day on/5 day off), 50 mg/kg IP QW, 50 mg/kg IP Q2D, and 50 mg/kg IP (2day on/5 day oft) dosing, and bodyweight changes observed in NOC/SCIDmice (E) for vehicle, 50 mg/kg IP QW, 50 mg/kg IP Q2D, and 50 mg/kg IP(2 day on/5 day off) dosing.

FIG. 7 depicts the decrease in STAT3 observed at 24 hours treatment withI-103 (A), the time-dependent inhibition of proliferation with I-103(B), the increase in activated Caspase 3 at 48 hours that leads to celldeath with I-103 treatment (C), and increase in subG1 cells observedwith I-103 treatment (D).

FIG. 8 depicts that a decrease of STAT3 by 90% using I-103 is necessaryto induce SU-DHL-1 apoptosis and inhibit cell growth.

FIG. 9 depicts a dose response curve showing I-111 degrading mutantSTAT3 (STAT D661Y) in HDLM-2 cell lines.

FIG. 10 depicts wash-out study results with I-103 at 24 hours (A) and 48hours (B).

FIG. 11 depicts degradation results of the reduction of STAT3 in STAT3mutants using I-83 (3 μM, 24 hr) in ectopically overexpressed HEK293cells showing Flag-STAT3 levels (% DMSO)(y-axis) for WT, D661Y (SH2),D661V (SH2), Y640F (SH2), and K392R (DBD) mutants (x-axis).

FIG. 12 depicts a dose response curve showing I-83 degrading mutantSTAT3 (STAT D661Y) in HDLM-2 cell lines.

FIG. 13 includes images of deep tandem mass tag (TMT) proteomicscatterplots in SU-DHL-1 (ALCL) at 8 hours showing −Log 10 p-value(y-axis) and Log 2 fold change at 150 nM, 350 nM, and 3.5 μM I-174 inDMSO (x-axis).

FIG. 14 depicts dose response curves and DC₅₀ results showing I-174 andI-94 mediated degradation in multiple ALK+ALCL cell lines.

FIG. 15 depicts dose response curves and IC₅₀ results showing I-174 andI-94 repression of STAT3-mediated gene expression in of SOCS3 and PD-L1in SU-DHL-1 cells.

FIG. 16 depicts dose response curves showing I-174 and I-94 mediatedgrowth inhibition in multiple ALK+ALCL cell lines.

FIG. 17 depicts that a decrease of STAT3 by 90% using I-174 and I-94 isnecessary to induce SU-DHL-1 apoptosis and inhibit cell growth.

FIG. 18 depicts wash-out study results with I-174 showing strong growthinhibition and potential cell death after 4 days (24 hours wash-out) andcomplete growth inhibition and cell death after 4 days (48 hourswash-out) in SU-DHL-1 cells.

FIG. 19 depicts ALK+ALCL SU-DHL-1 mouse xenographs and K_(D) resultsusing I-174 for STAT3 degradation with tumor volume median (mm³) overdays (post randomization) for vehicle, 2.5, 5, 10 and 25 mg/kg (mpk)dosing.

FIG. 20 includes ALK+ALCL SUP-M2 xenograph results using I-174 for STAT3degradation with tumor volume median (mm³) over days(post-randomization) for vehicle, 3 mg/kg IV 2 d on/5 d off, 10 mg/kg IV2 d on/5 d off, 30 mg/kg IV 2 d on/5 d off, and 30 mg/kg IC QW dosing(upper graph) and body weight (g) over day (post-randomization) foranimal FD 10 mg/kg 2 d on/5 d off and 30 mg/kg 2 d on/5 d off (lowergraph).

FIG. 21 depicts dose-response curves in a STAT3-HiBiT live cell assay inA549 cells using I-174 and I-94 with STAT3 protein (% control)(y-axis)over compound concentration (nM)(x-axis) at 0.5, 1, 2, 4, 6, 8, 24, and48 hours.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas degraders and/or inhibitors of one or more STAT proteins. In someembodiments, a provided compound degrades and/or inhibits one or more ofSTAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6.

In certain embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:STAT is a STAT binding moiety capable of binding to one or more ofSTAT1, STAT2, STAT3, STAT4,

STAT5A, STAT5B, or STAT6;

L is a bivalent moiety that connects STAT to LBM; andLBM is a ligase binding moiety.

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:STAT is a STAT binding moiety capable of binding to one or more ofSTAT1, STAT2, STAT3, STAT4,

STAT5A, STAT5B, or STAT6;

L is a bivalent moiety that connects STAT to DIM; andDIM is a degradation inducing moiety.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule. Insome embodiments, a carbocyclic ring may be a 5-12 membered bicyclic,bridged bicyclic, or spirocyclic ring. A carbocyclic ring may includeone or more oxo (═O) or thioxo (═S) substituent. Suitable aliphaticgroups include, but are not limited to, linear or branched, substitutedor unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof suchas (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or *NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. Aheterocyclic ring may include one or more oxo (═O) or thioxo (═S)substituent. The term “heterocyclylalkyl” refers to an alkyl groupsubstituted by a heterocyclyl, wherein the alkyl and heterocyclylportions independently are optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄₀C(O)R^(o);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o); —(CH₂)₀₋₄C(O)NR^(o)₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o), —(CH₂)₀₋₄OC(O)NR^(o) ₂;—C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄₀S(O)₂R^(o); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o))₂; SiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂)₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate. In some embodiments, the provided compounds are purified insalt form for convenience and/or ease of purification, e.g., using anacidic or basic mobile phase during chromatography. Salts forms of theprovided compounds formed during chromotagraphic purification arecomtemplated herein (e.g., diammonium salts) and are readily apparent tothose having skill in the art.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention

As used herein, the term “provided compound” refers to any genus,subgenus, and/or species set forth herein.

The term “prodrug” refers to a compound that is made more active invivo. The present compounds can also exist as prodrugs, as described inHydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, andEnzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich,Switzerland 2003). Prodrugs of the compounds described herein arestructurally modified forms of the compound that readily undergochemical changes under physiological conditions to provide the compound.Additionally, prodrugs can be converted to the compound by chemical orbiochemical methods in an ex vivo environment. For example, prodrugs canbe slowly converted to a compound when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the compound, or parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. A wide variety of prodrug derivatives are known inthe art, such as those that rely on hydrolytic cleavage or oxidativeactivation of the prodrug. An example, without limitation, of a prodrugwould be a compound which is administered as an ester (the “prodrug”),but then is metabolically hydrolyzed to the carboxylic acid, the activeentity. Additional examples include peptidyl derivatives of a compound.The term “therapeutically acceptable prodrug,” refers to those prodrugsor zwitterions which are suitable for use in contact with the tissues ofpatients without undue toxicity, irritation, and allergic response, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits an STAT protein with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM.

As used herein, the term “degrader” is defined as a heterobifunctionalcompound that binds to and/or inhibits both an STAT protein and an E3ligase with measurable affinity resulting in the ubiquitination andsubsequent degradation of the STAT protein. In certain embodiments, adegrader has an DC₅₀ of less than about 50 μM, less than about 1 μM,less than about 500 nM, less than about 100 nM, less than about 10 nM,or less than about 1 nM. As used herein, the term “monovalent” refers toa degrader compound without an appended E3 ligase binding moiety.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in a STAT protein activity between asample comprising a compound of the present invention, or compositionthereof, and a STAT protein, and an equivalent sample comprising a STATprotein, in the absence of said compound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:STAT is a STAT protein binding moiety capable of binding to one or moreof STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6;L is a bivalent moiety that connects STAT to LBM; andLBM is a E3 ubiquitin ligase binding moiety.

In some embodiments, the present invention provides a compound offormula L:

or a pharmaceutically acceptable salt thereof, wherein:STAT is a STAT3 binding moiety;L is a bivalent moiety that connects STAT to LBM; andLBM is a cereblon E3 ubiquitin ligase binding moiety.

As described above, in certain embodiments, the present inventionprovides a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:STAT is a STAT protein binding moiety capable of binding to one or moreof STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6;L is a bivalent moiety that connects STAT to DIM; andDIM is a degradation inducing moiety.

In some embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:STAT is a STAT3 binding moiety;L is a bivalent moiety that connects STAT to DIM; andDIM is LBM, a lysine mimetic, or a hydrogen atom.

Ligase Binding Moiety (LBM)

In some embodiments, LBM is an E3 ligase ligand. Such E3 ligase ligandsare well known to one of ordinary skill in the art and include thosedescribed in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55,1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO2017/176708, US 2017/0281784, WO 2017/161119, WO 2017/176957, WO2017/176958, WO 2015/160845, US 2015/0291562, WO 2016/197032, WO2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684, WO2013/106643, US 2014/0356322, WO 2002/020740, US 2002/0068063, WO2012/078559, US 2014/0302523, WO 2012/003281, US 2013/0190340, US2016/0022642, WO 2014/063061, US 2015/0274738, WO 2016/118666, US2016/0214972, WO 2016/149668, US 2016/0272639, WO 2016/169989, US2018/0118733, WO 2016/197114, US 2018/0147202, WO 2017/011371, US2017/0008904, WO 2017/011590, US 2017/0037004, WO 2017/079267, US2017/0121321, WO 2017/117473, WO 2017/117474, WO 2013/106646, WO2014/108452, WO 2017/197036, WO 2017/197046, WO 2017/197051, WO2017/197055, and WO 2017/197056 each of, the entirety of each of whichis herein incorporated by reference.

As defined herein and described below, wherein a formula is depictedusing square brackets, e.g.,

L is attached to a modifiable carbon, oxygen, or nitrogen atom withinDIM or LBM including substitution or replacement of a defined group inDIM or LBM.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-a-1, I-a-2, I-a-3, I-a-4,I-a-5, I-a-6, I-a-7, I-a-8, I-a-9, or I-a-10 respectively:

or a compound of formula I-a′-1, I-a′-2, I-a′-3, I-a′-4, I-a′-5, I-a′-6,I-a′-7, I-a′-8, I-a′-9, or I-a′-10 respectively:

or a compound of formula I-a″-1, I-a″-2, I-a″-3, I-a″-4, I-a″-5, I-a″-6,I-a″-7, I-a″-8, I-a″-9, or I-a″-respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables

X, X₁, X₂, Y, R₁, R₃, R_(3′), R₄, R₅, t, m and n is as defined anddescribed in WO 2017/007612 and US 2018/0134684, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-b-1, I-b-2, I-b-3, I-b-4,I-b-5, or I-b-6 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables A, G, G′, Q₁, Q₂, Q₃, R, R′, W, X, Y, Z and n is asdefined and described in WO 2016/197114 and US 2018/0147202, theentirety of each of which is herein incorporated by reference.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-c:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   Ring A is a bi- or tricyclic ring selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;-   each R₄ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   L is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S(O)₂— or    —(C)═CH—;-   m is 0, 1, 2, 3 or 4;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(m) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, a compound of formula I-c above is provided as acompound of formula I-c′ or formula I-c″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring A, L, L¹, R¹, R², X¹, X², X³, and m is as definedabove.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-d:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   Ring A is a bi- or tricyclic ring selected from

wherein Ring B is other than imidazo or benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;-   each R₄ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, 2, 3 or 4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(m) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, the compound of formula I-d above is provided as acompound of formula I-d′ or formula I-d″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring A, L, R¹, R², X¹, X², X³, and m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-e:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, or an optionally substituted C₁₋₄ aliphatic;-   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   Ring A is a bi- or tricyclic ring selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;-   each R₄ is independently hydrogen, —R, halogen, —CN, —NO₂, —OR, —SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, 2, 3 or 4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(m) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R group.

In some embodiments, the compound of formula I-e above is provided as acompound of formula I-e′ or formula I-e″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring A, L, R¹, R², X¹, and m is as defined above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-f:

or a pharmaceutically acceptable salt thereof, wherein, L and STAT areas defined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each of R² and R^(3a) is independently hydrogen, deuterium, —R⁶,    halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; Ring D is    selected from a 6-membered aryl, 6-membered heteroaryl containing    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, 5 to 7-membered saturated or partially unsaturated    carbocyclyl, 5 to 7-membered saturated or partially unsaturated    heterocyclyl ring with 1-3 heteroatoms independently selected from    boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   each R₄ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   L is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S(O)₂— or    —(C)═CH—;-   m is 0, 1, 2, 3 or 4;-   n is 0, 1, 2, 3 or 4;-   p is 0 or 1, wherein when p is 0, the bond connecting Ring C and    Ring D is connected to

and

-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-f above is provided as acompound of formula I-f′ or formula I-f″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of STAT, Ring C, Ring D, L, L¹, R¹, R², R^(3a), X¹, X², X³,        n, m, and p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-g:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each of R² and R^(3a) is independently hydrogen, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   Ring D is selected from 6-membered aryl, 6-membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   each R₄ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, or 2;-   n is 0, 1, 2, 3 or 4;-   p is 0 or 1, wherein when p is 0, the bond connecting Ring C and    Ring D is connected to

and

-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-g above is provided as acompound of formula I-g′ or formula I-g″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring C, Ring D, L, R¹, R², R^(3a), X¹, n, m, and p is asdefined above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-h:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each or R² and R^(3a) is independently hydrogen, deuterium, —R⁶,    halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   Ring D is selected from 6-membered aryl, 6-membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   each R₄ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   L is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S(O)₂— or    —(C)═CH—;-   m is 0, 1, 2, 3 or 4;-   n is 0, 1, 2, 3 or 4;-   p is 0 or 1; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-h above is provided as acompound of formula I-h′ or formula I-h″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring C, Ring D, L, L¹, R¹, R², R^(3a), X¹, X², X³, m, n,and p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-i:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each of R², R^(3a), and R⁴ is independently hydrogen, —R⁶, halogen,    —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,    —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   Ring D is selected from 6-membered aryl, 6-membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, or 2;-   n is 0, 1, 2, 3, or 4;-   p is 0 or 1; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-i above is provided as acompound of formula I-i′ or formula I-i″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring C, Ring D, L, R¹, R², R^(3a), X¹, m, n, and p is asdefined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-j:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring E, Ring F, and Ring G is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur, wherein each    of Ring E, Ring F, and Ring G is independently and optionally    further substituted with 1-2 oxo groups;-   L is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S(O)₂— or    —(C)═CH—; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G are fused to RingF.

Where a point of attachment of —(R²)_(m) is depicted on Ring E, Ring F,or Ring G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring E or Ring G are fused to Ring F.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the carbon atom to which Ring E or Ring G are fused toRing F.

In some embodiments, a compound of formula I-j above is provided as acompound of formula I-j′ or formula I-j″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring E, Ring F, Ring G, L, L¹, R¹, R², X¹, X², X³, and mis as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-k:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring E, Ring F, and Ring G is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur, wherein each    of Ring E, Ring F, and Ring G is independently and optionally    further substituted with 1-2 oxo groups; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of is depicted on Ring E, Ring F, or Ring G,it is intended, and one of ordinary skill in the art would appreciate,that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G are fused to RingF.

Where a point of attachment of —(R²)_(m) is depicted on Ring E, Ring F,or Ring G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring E or Ring G are fused to Ring F.

In some embodiments, a compound of formula I-k above is provided as acompound of formula I-k′ or formula I-k″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, L, Ring E, Ring F, Ring G, L, R¹, R², X¹, and m is asdefined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-1:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring E is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-9 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring E is optionally further substituted    with 1-2 oxo groups;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S(O)₂— or    —(C)═CH—;-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E or Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring E and RingH, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring E or Ring H including thecarbon atom to which Ring E and Ring H are fused.

Where a point of attachment of

is depicted on Ring E and Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

In some embodiments, a compound of formula I-1 above is provided as acompound of formula I-l′ or formula I-l″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring E, Ring H, L, L¹, R¹, R², X¹, X², X³, and m is asdefined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-m:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring E is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl ring with 1-3 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, or    5-membered heteroaryl with 1-4 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring H is a ring selected from a 7-9 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, wherein Ring E is optionally further substituted with 1-2    oxo groups; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E or Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring E and RingH, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring E or Ring H including thecarbon atom to which Ring E and Ring H are fused.

Where a point of attachment of

is depicted on Ring E and Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

In some embodiments, a compound of formula I-m above is provided as acompound of formula I-m′ or formula I-m″.

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring E, Ring H, L, R¹, R², X¹, and m is as defined above.

In some embodiments, a compound of formula I-m above is provided as acompound of formula I-m-1:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, L, Ring E, X¹, R¹, R², and m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-n:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring I and J is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring K is a fused ring selected from a 6-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups; L¹ is a covalent bond or a C₁₋₃ bivalent    straight or branched saturated or unsaturated hydrocarbon chain    wherein 1-2 methylene units of the chain are independently and    optionally replaced with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—,    —C(F)₂—, —N(R)—, —S(O)₂— or —(C)═CH—; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring I, Ring J,and Ring K, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring I, Ring J, or Ring K,including the carbon atom to which Ring I, Ring J, and Ring K are fused.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

In some embodiments, a compound of formula I-n above is provided as acompound of formula I-n′ or formula I-n″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring I, Ring J, Ring K, L, L¹, R¹, R², X¹, X², X³, and mis as defined above.

In certain embodiments, the present invention provides a compound offormula I-o:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring I and J is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl ring with    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring K is a fused ring selected from a 6-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring I, Ring J,and Ring K, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring I, Ring J, or Ring K,including the carbon atom to which Ring I, Ring J, and Ring K are fused.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

In some embodiments, a compound of formula I-o above is provided as acompound of formula I-o′ or formula I-o″:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, Ring I, Ring J, Ring K, L, R¹, R², X¹, and m is as definedabove.

In some embodiments, a compound of formula I-o above is provided as acompound of formula I-o-1:

or a pharmaceutically acceptable salt thereof, wherein:each of STAT, L, Ring I, Ring K, X¹, R¹, R², and m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-o-2 or I-o-3:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein:

-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,    —N(R)P(O)(NR₂)₂, or—N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring E, Ring F, and Ring G is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur, wherein each    of Ring E, Ring F, and Ring G is independently and optionally    further substituted with 1-2 oxo groups;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;    and-   R⁴, R¹⁰, R¹¹, R¹⁵, W¹, W², and X is as defined in WO 2019/099868,    the entirety of each of which is herein incorporated by reference.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G are fused to RingF.

Where a point of attachment of —(R²)_(m) is depicted on Ring E, Ring F,or Ring G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring E or Ring G are fused to Ring F.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the carbon atom to which Ring E or Ring G are fused toRing F.

As defined above and described herein, X¹ is a bivalent moiety selectedfrom a covalent bond, —CH₂—, —C(R)₂—, —C(O)—, —C(S)—, —CH(R)—,—CH(CF₃)—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S(O)—, —S(O)₂—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CH₂—. In some embodiments, X¹ is —C(R)₂—. In some embodiments, X¹ is—C(O)—. In some embodiments, X¹ is —C(S)—. In some embodiments, X¹ is—CH(R)—. In some embodiments, X¹ is —CH(CF₃)—. In some embodiments, X¹is —P(O)(OR)—. In some embodiments, X¹ is —P(O)(R)—. In someembodiments, X¹ is —P(O)(NR₂)—. In some embodiments, X¹ is —S(O)—. Insome embodiments, X¹ is —S(O)₂—. In some embodiments, X¹ is

In some embodiments, X¹ is selected from those depicted in Table 1,below.

As defined above and described herein, X² is a carbon atom or siliconatom.

In some embodiments, X² is a carbon atom. In some embodiments, X² is asilicon atom.

In some embodiments, X² is selected from those depicted in Table 1,below.

As defined above and described herein, X³ is a bivalent moiety selectedfrom —CH₂—, —C(R)₂—, —N(R)—, —CF₂—, —CHF—, —S—, —CH(R)—, —Si(R₂)—, or—O—.

In some embodiments, X³ is —CH₂—. In some embodiments, X¹ is —C(R)₂—. Insome embodiments, X³ is —N(R)—. In some embodiments, X³ is —CF₂—. Insome embodiments, X³ is —CHF—. In some embodiments, X³ is —S—. In someembodiments, X³ is —CH(R)—. In some embodiments, X³ is —Si(R₂)—. In someembodiments, X³ is —O—.

In some embodiments, X³ is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, an optionally substitutedC₁₋₄ aliphatic, or R¹ and X¹ or X4 are taken together with theirintervening atoms to form a 5-7 membered saturated, partiallyunsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms, independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is halogen. In some embodiments, R¹is —CN. In some embodiments, R¹ is —OR. In some embodiments, R¹ is —SR.In some embodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R.In some embodiments, R¹ is —NR₂. In some embodiments, R¹ is —P(O)(OR)₂.In some embodiments, R¹ is —P(O)(NR₂)OR. In some embodiments, R¹ is—P(O)(NR₂)₂. In some embodiments, R¹ is —Si(OH)₂R. In some embodiments,R¹ is —Si(OH)(R)₂. In some embodiments, R¹ is —Si(R)₃. In someembodiments, R¹ is an optionally substituted C₁₋₄ aliphatic. In someembodiments, R¹ and X¹ or X4 are taken together with their interveningatoms to form a 5-7 membered saturated, partially unsaturated,carbocyclic ring or heterocyclic ring having 1-3 heteroatoms,independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,deuterium, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from boron, nitrogen,oxygen, silicon, and sulfur, or two R groups on the same nitrogen aretaken together with their intervening atoms to form a 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is deuterium.In some embodiments, R is optionally substituted C₁₋₆ aliphatic. In someembodiments, R is optionally substituted phenyl. In some embodiments, Ris optionally substituted 4-7 membered saturated or partiallyunsaturated heterocyclic having 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments,R is optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur. In some embodiments, two R groups on the samenitrogen are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined above and described herein, each of R² and R^(3a) isindependently hydrogen, deuterium, —R⁶, halogen, —CN, —NO₂, —OR,—Si(OH)₂R, —Si(OH)R₂, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,—C(R)₂N(R)C(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂-, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,—N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R.

In some embodiments, R² and R^(3a) is independently hydrogen. In someembodiments, R² and R^(3a) is independently deuterium. In someembodiments, R² and R^(3a) is independently —R. In some embodiments, R²and R^(3a) is independently halogen. In some embodiments, R² and R^(3a)is independently —CN. In some embodiments, R² and R^(3a) isindependently —NO₂. In some embodiments, R² and R^(3a) is independently—OR. In some embodiments, R² and R^(3a) is independently —Si(OH)₂R. Insome embodiments, R² and R^(3a) is independently —Si(OH)R₂. In someembodiments, R² and R^(3a) is independently —SR. In some embodiments, R²and R^(3a) is independently —NR₂. In some embodiments, R² and R^(3a) isindependently —SiR₃. In some embodiments, R² and R^(3a) is independently—S(O)₂R. In some embodiments, R² and R^(3a) is independently —S(O)₂NR₂.In some embodiments, R² and R^(3a) is independently —S(O)R. In someembodiments, R² and R^(3a) is independently —C(O)R. In some embodiments,R² and R^(3a) is independently —C(O)OR. In some embodiments, R² andR^(3a) is independently —C(O)NR₂. In some embodiments, R² and R^(3a) isindependently —C(O)N(R)OR. In some embodiments, R² and R^(3a) isindependently —C(R)₂N(R)C(O)R. In some embodiments, R² and R^(3a) isindependently —C(R)₂N(R)C(O)NR₂. In some embodiments, R² and R^(3a) isindependently —OC(O)R. In some embodiments, R² and R^(3a) isindependently —OC(O)NR₂. In some embodiments, R² and R^(3a) isindependently —OP(O)R₂. In some embodiments, R² and R^(3a) isindependently —OP(O)(OR)₂. In some embodiments, R² and R^(3a) isindependently —OP(O)(OR)NR₂. In some embodiments, R² and R^(3a) isindependently —OP(O)(NR₂)₂-. In some embodiments, R² and R^(3a) isindependently —N(R)C(O)OR. In some embodiments, R² and R^(3a) isindependently —N(R)C(O)R. In some embodiments, R² and R^(3a) isindependently —N(R)C(O)NR₂. In some embodiments, R² and R^(3a) isindependently —NP(O)R₂. In some embodiments, R² and R^(3a) isindependently —N(R)P(O)(OR)₂. In some embodiments, R² and R^(3a) isindependently —N(R)P(O)(OR)NR₂. In some embodiments, R² and R^(3a) isindependently —N(R)P(O)(NR₂)₂. In some embodiments, R² and R^(3a) isindependently —N(R)S(O)₂R.

In some embodiments, R² and R^(3a) is independently —OH. In someembodiments, R² and R^(3a) is independently —NH₂. In some embodiments,R² and R^(3a) is independently —CH₂NH₂. In some embodiments, R² andR^(3a) is independently —CH₂NHCOMe. In some embodiments, R² and R^(3a)is independently —CH₂NHCONHMe. In some embodiments, R² and R^(3a) isindependently —NHCOMe. In some embodiments, R² and R^(3a) isindependently —NHCONHEt. In some embodiments, R² and R^(3a) isindependently —SiMe₃. In some embodiments, R² and R^(3a) isindependently —SiMe₂OH. In some embodiments, R² and R^(3a) isindependently —SiMe(OH)₂. In some embodiments R² and R^(3a) isindependently

In some embodiments, R² and R^(3a) is independently Br. In someembodiments, R² and R^(3a) is independently Cl. In some embodiments, R²and R^(3a) is independently F. In some embodiments, R² and R^(3a) isindependently Me. In some embodiments, R² and R^(3a) is independently—NHMe. In some embodiments, R² and R^(3a) is independently —NMe₂. Insome embodiments, R² and R^(3a) is independently —NHCO₂Et. In someembodiments, R² and R^(3a) is independently —CN. In some embodiments, R²and R^(3a) is independently —CH₂Ph. In some embodiments, R² and R^(3a)is independently —NHCO₂tBu. In some embodiments, R² and R^(3a) isindependently —CO₂tBu. In some embodiments, R² and R^(3a) isindependently —OMe. In some embodiments, R² and R^(3a) is independently—CF₃.

In some embodiments, R² or R^(3a) is selected from those depicted inTable 1, below.

As defined above and described herein, R₃ is hydrogen, deuterium,halogen, —CN, —NO₂, —OR, —NR₂, —SR, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)NR(OR), —OC(O)R, —OC(O)NR₂, —OP(O)(OR)₂,—OP(O)(NR₂)₂, —OP(O)(OR)NR₂, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR₂,—N(R)S(O)₂R, —N(R)S(O)₂NR₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, or—Si(R)₃.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isdeuterium. In some embodiments, R³ is halogen. In some embodiments, R³is —CN. In some embodiments, R³ is —NO₂. In some embodiments, R³ is —OR.In some embodiments, R³ is —NR₂. In some embodiments, R³ is —SR. In someembodiments, R³ is —S(O)₂R. In some embodiments, R³ is —S(O)₂NR₂. Insome embodiments, R³ is —S(O)R. In some embodiments, R³ is —C(O)R. Insome embodiments, R³ is —C(O)OR. In some embodiments, R³ is —C(O)NR₂. Insome embodiments, R³ is —C(O)NR(OR). In some embodiments, R³ is —OC(O)R.In some embodiments, R³ is —OC(O)NR₂. In some embodiments, R³ is—OP(O)(OR)₂. In some embodiments, R³ is —OP(O)(NR₂)₂. In someembodiments, R³ is —OP(O)(OR)NR₂. In some embodiments, R³ is —N(R)C(O)R.In some embodiments, R³ is —N(R)C(O)OR. In some embodiments, R³ is—N(R)C(O)NR₂. In some embodiments, R³ is —N(R)S(O)₂R. In someembodiments, R³ is —N(R)S(O)₂NR₂. In some embodiments, R³ is—N(R)P(O)(OR)₂. In some embodiments, R³ is —N(R)P(O)(OR)NR₂. In someembodiments, R³ is —P(O)(OR)₂. In some embodiments, R³ is —P(O)(NR₂)OR.In some embodiments, R³ is —P(O)(NR₂)₂. In some embodiments, R³ is—Si(OH)₂R. In some embodiments, R³ is —Si(OH)(R)₂. In some embodiments,R³ is —Si(R)₃.

In some embodiments, R³ is methyl. In some embodiments, R³ is —OCH₃. Insome embodiments, R³ is chloro.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined above and described herein, each R⁴ is independentlyhydrogen, deuterium, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,—S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R,—P(O)(OR)₂, —P(O)(NR₂)OR, or —P(O)(NR₂)₂.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is —R⁶. Insome embodiments, R⁴ is halogen. In some embodiments, R⁴ is —CN. In someembodiments, R⁴ is —NO₂. In some embodiments, R⁴ is —OR. In someembodiments, R⁴ is —SR. In some embodiments, R⁴ is —NR₂. In someembodiments, R⁴ is —S(O)₂R. In some embodiments, R⁴ is —S(O)₂NR₂. Insome embodiments, R⁴ is —S(O)R. In some embodiments, R⁴ is —C(O)R. Insome embodiments, R⁴ is —C(O)OR. In some embodiments, R⁴ is —C(O)NR₂. Insome embodiments, R⁴ is —C(O)N(R)OR. In some embodiments, R⁴ is —OC(O)R.In some embodiments, R⁴ is —OC(O)NR₂. In some embodiments, R⁴ is—N(R)C(O)OR. In some embodiments, R⁴ is —N(R)C(O)R. In some embodiments,R⁴ is —N(R)C(O)NR₂. In some embodiments, R⁴ is —N(R)S(O)₂R. In someembodiments, R⁴ is —P(O)(OR)₂. In some embodiments, R⁴ is —P(O)(NR₂)OR.In some embodiments, R⁴ is —P(O)(NR₂)₂.

In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is ethyl. Insome embodiments, R⁴ is cyclopropyl.

In some embodiments, R⁴ is selected from those depicted in Table 1,below.

As defined above and described herein, R⁵ is hydrogen, deuterium, anoptionally substitute C₁₋₄ aliphatic, or —CN.

In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ isdeuterium. In some embodiments, R⁵ is an optionally substituted C₁₋₄aliphatic. In some embodiments, R⁵ is —CN.

In some embodiments, R⁵ is selected from those depicted in Table 1,below.

As defined above and described herein, each R⁶ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R⁶ is an optionally substituted phenyl. In someembodiments, R⁶ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, andsulfur. In some embodiments, R⁶ is an optionally substituted 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R⁶ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a bi- or tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, Ring B is a fused ring selectedfrom 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 5 to 7-memberedsaturated or partially unsaturated carbocyclyl, 5 to 7-memberedsaturated or partially unsaturated heterocyclyl ring with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;

In some embodiments, Ring B is a fused 6-membered aryl. In someembodiments, Ring B is a fused 6-membered heteroaryl containing 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring B is a fused 5 to 7-membered saturated orpartially unsaturated carbocyclyl. In some embodiments, Ring B is fused5 to 7-membered saturated or partially saturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, Ring B is fused 5-memberedheteroaryl with 1-4 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is selected from

In some embodiments, Ring B is selected from those depicted in Table 1,below.

As defined above and described herein, Ring C is a mono- or bicyclicring selected from

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is a mono- or bicyclic ring selected from

In some embodiments, Ring C is selected from

In some embodiments, Ring C is selected from

In some embodiments, Ring C is selected from those depicted in Table 1,below.

As defined above and described herein, Ring D is a ring selected from6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 5 to 7-memberedsaturated or partially unsaturated carbocyclyl, 5 to 7-memberedsaturated or partially unsaturated heterocyclyl ring with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur;

In some embodiments, Ring D is a 6-membered aryl. In some embodiments,Ring D is a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring D is a 5 to 7-membered saturated or partiallyunsaturated carbocyclyl. In some embodiments, Ring D is 5 to 7-memberedsaturated or partially saturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur.In some embodiments, Ring D is 5-membered heteroaryl with 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur.

In some embodiments, Ring D is selected from those depicted in Table 1,below.

As defined above and described herein, each of Ring E, Ring F, and RingG is independently a fused ring selected from 6-membered aryl,6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur, wherein each of Ring E, Ring F, and Ring G isindependently and optionally further substituted with 1-2 oxo groups.

In some embodiments, each Ring E, Ring F, and Ring G is independently a6-membered aryl. In some embodiments, each Ring E, Ring F, and Ring G isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each Ring E, Ring F, and Ring G is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each Ring E, Ring F, and Ring G is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each Ring E, Ring F, and Ring Gis independently a 5-membered heteroaryl with 1-4 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, each of Ring E, Ring F, and Ring G is independently andoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments,In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, each Ring E and Ring G is independently

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is selected from thosedepicted in Table 1, below.

As defined above and described herein, Ring H is a ring selected from a7-9 membered saturated or partially unsaturated carbocyclyl orheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E isoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring H is a ring selected from a 7-9 memberedsaturated or partially unsaturated carbocyclyl or heterocyclyl ring with1-3 heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, wherein Ring H is optionally further substitutedwith 1-2 oxo groups.

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring E and Ring H is

In some embodiments, Ring E and Ring H is selected from those depictedin Table 1, below.

As defined above and described herein, each of Ring I and Ring J isindependently a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur

In some embodiments, each of Ring I and Ring J is independently a6-membered aryl. In some embodiments, each of Ring I and Ring J isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each of Ring I and Ring J is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each of Ring I and Ring J is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl ring with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each of Ring I and Ring J isindependently a 5-membered heteroaryl with 1-3 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring I and Ring J is independently

In some embodiments, each Ring I and Ring J is independently

In some embodiments, each Ring I and Ring J is independently

In some embodiments, each Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is independently is

In some embodiments, Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is independently

As defined above and described herein, Ring K is a fused ring selectedfrom a 6-12 membered saturated or partially unsaturated carbocyclyl orheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H isoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring K is a fused ring selected from a 6-12membered saturated or partially unsaturated carbocyclyl. In someembodiments, Ring K is a 6-12 membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur. In someembodiments, Ring K is optionally further substituted with 1-2 oxogroups.

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

some some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring I, Ring J, and Ring K is

In some embodiments, Ring I, Ring J, and Ring K is selected from thosedepicted in Table 1, below.

As defined above and described here, L¹ is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—,—N(R)—, —S(O)₂- or —(C)═CH—;

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is aC₁₋₃ aliphatic. In some embodiments, L¹ is —CH₂—. In some embodiments,L¹ is —C(D)(H)—. In some embodiments, L¹ is —C(D)₂-. In someembodiments, L¹ is —CH₂CH₂—. In some embodiments, L¹ is —NR—. In someembodiments, L¹ is —CH₂NR—. In some embodiments, L¹ is or —O—. In someembodiments, L¹ is —CH₂O—. In some embodiments, L¹ is —S—. In someembodiments, L¹ is —OC(O)—. In some embodiments, L¹ is —C(O)O—. In someembodiments, L¹ is —C(O)—. In some embodiments, L¹ is —S(O)—. In someembodiments, L¹ is —S(O)₂—. In some embodiments, L¹ is —NRS(O)₂—. Insome embodiments, L¹ is —S(O)₂NR—. In some embodiments, L¹ is —NRC(O)—.In some embodiments, L¹ is —C(O)NR—.

In some embodiments, Ring L¹ is selected from those depicted in Table 1,below.

As defined above and described herein,

is a single or double bond.

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

In some embodiments,

is selected from those depicted in Table 1, below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8. In some embodiments, mis 9. In some embodiments, m is 10. In some embodiments, m is 11. Insome embodiments, m is 12. In some embodiments, m is 13. In someembodiments, m is 14. In some embodiments, m is 15. In some embodiments,m is 16.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined above and described herein, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In some embodiments, n is selected from those depicted in Table 1,below.

As defined above and described herein, p is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, p is selected from those depicted in Table 1,below.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-p-1, I-p-2, or I-p-3respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described herein, and wherein each of the variablesR¹, R², R⁴, R⁵, R¹⁰, R¹¹, R¹⁴, R¹⁷, W¹, W², X,

, and n is as defined in WO 2017/197051 which is herein incorporated byreference in its entirety and wherein

is attached to R¹, the ring formed by combining R¹ and R², or R¹⁷ at thesite of attachment of R¹² as defined in WO 2017/197051 such that

takes the place of the R¹² substituent.

In some embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-q-1, I-q-2, I-q-3, orI-q-4, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described herein, and wherein each of the variablesR¹, R⁴, R¹⁰, R¹¹, R¹⁴, R¹⁶, W¹, W², X,

, and n is as defined in WO 2018/237026, the entirety of each of whichis herein incorporated by reference, and wherein

is attached to R¹ or R¹⁶ at the site of attachment of R¹² as defined inWO 2018/237026, such that

takes the place of the R¹² substituent.

In some embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-r-1 or I-r-3,respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described herein, and wherein each of the variablesR¹, R¹⁴, and R¹⁶ is as defined in WO 2018/237026, the entirety of eachof which is herein incorporated by reference, and wherein

is attached to R¹ or R¹⁶ at the site of attachment of R¹² as defined inWO 2018/237026, such that

takes the place of the R¹² substituent.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-s-1, I-s-2, I-s-3, I-s-4,I-s-5, I-s-6, I-s-7, or I-s-8:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables Ar, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, A, L, x, y, and

is as described and defined in WO 2017/161119, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-t:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables A, B, C, W, X, Y, and Z is as described and defined inU.S. Pat. No. 5,721,246, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-t-1:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R₁, R₂, and n is as described and defined in WO2019/043214, the entirety of each of which is herein incorporated byreference.

In some embodiments, LBM is a IAP E3 Ubiquitin ligase binding moietyrecited in Varfolomeev, E. et al., IAP Antagonists InduceAutoubiquitination of c-IAPs, NF-κB activation, and TNFα- DependentApoptosis, Cell, 2007, 131(4): 669-81, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-u-1, I-u-2, I-u-3, I-u-4, orI-u-5 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R^(1′), R^(2′), R^(3′), X, and X¹ is as defined anddescribed in WO 2013/106643 and US 2014/0356322, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-v-1, I-v-2, I-v-3, I-v-4, I-v-5or I-v-6 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R^(1′), R^(2′), R^(3′), R₅, R₆, R₇, R₉, R₁₀, R₁₁, R₁₄,R₁₅, R₁₆, R₁₇, R₂₃, R₂₅, E, G, M, X, X¹, Y, Z₁, Z₂, Z₃, Z₄, and o is asdefined and described in WO 2016/149668 and US 2016/0272639, theentirety of each of which is herein incorporated by reference.

As used herein, depiction of brackets around any LBM

means that the

moiety is covalently attached to said LBM at any available modifiablecarbon, nitrogen, oxygen, or sulfur atom. For purposes of clarity and byway of example, such available modifiable carbon, nitrogen, oxygen, orsulfur atoms in the following LBM compound structure are depicted below,wherein each wavy bond defines the point of attachment to said

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-w-1, I-w-2, or I-w-3respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R^(p), R₉, R₁₀, R₁₁, R_(14a), R_(14b), R₁₅, R₁₆, W³, W⁴,W⁵, X¹, X², and o is as defined and described in WO 2016/118666 and US2016/0214972, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase bindingmoiety thereby forming a compound of formula I-x-1, I-x-2, I-x-3, I-x-4,I-x-5, I-x-6, or I-x-7 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables A¹, A², A³, R⁵, G and Z is as defined and described in WO2017/176958.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moietythereby forming a compound of formula I-x′-1, I-x″-1, I-x′-2, I-x″-2,I-x′-3, I-x″-3, I-x′-4, I-x″-4, I-x′-7 or I-x″-7 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables A¹, A², A³, R⁵, G and Z is as defined and described in WO2017/176958, the entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a MDM2 (i.e. human double minute 2 or HDM2) E3ligase binding moiety thereby forming a compound of formula I-y-1,I-y-2, I-y-3, I-y-4, I-y-5, I-y-6, I-y-7, I-y-8, I-y-9, I-y-10, I-y-11,I-y-12, I-y-13, I-y-14, I-y-15, I-y-16, I-y-17, or I-y-18 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇,R₂₈, R_(1′), R_(2′), R_(3′), R_(4′), R_(5′), R_(6′), R_(7′), R₈, R₉,R_(10′), R^(11′), R_(12′), R_(1″), A, A′, A″, X, Y, and Z is as definedand described in WO 2017/011371 and US 2017/0008904, the entirety ofeach of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an IAP E3 ubiquitin ligase binding moietythereby forming a compound of formula I-z-1, I-z-2, I-z-3, or I-z-4respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, is as defined anddescribed in WO 2017/011590 and US 2017/0037004, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3ubiquitin ligase binding moiety; thereby forming a compound of formulaI-aa-1, I-aa-2, or I-aa-3:

or a pharmaceutically acceptable salt thereof, wherein L and STAT is asdefined above and described in embodiments herein, and wherein:each of X¹, X^(2a), and X^(3a) is independently a bivalent moietyselected from a covalent bond, —CH₂—, —C(O)—, —C(S)—, or;

-   each of X⁴ and X⁵ is independently a bivalent moiety selected from    —CH₂—, —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, or an optionally substituted C₁₋₄ aliphatic;-   each of R², R^(3b), and R^(4a) is independently hydrogen, —R⁶,    halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R^(5a) is hydrogen or C₁₋₆ aliphatic;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring A^(a) is a fused ring selected from 6-membered aryl containing    0-2 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl,    5 to 7-membered partially saturated heterocyclyl with 1-2    heteroatoms independently selected from nitrogen, oxygen or sulfur,    or 5-membered heteroaryl with 1-3 heteroatoms independently selected    from nitrogen, oxygen or sulfur;-   Ring B^(a) is selected from 6-membered aryl containing 0-2 nitrogen    atoms or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Ring C^(a) is a selected from 6-membered aryl containing 0-2    nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   m is 0, 1, 2, 3 or 4;-   o is 0, 1, 2, 3 or 4;-   q is 0, 1, 2, 3 or 4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I-aa, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-aa′-1 or I-aa″-1:

or a pharmaceutically acceptable salt thereof, wherein STAT, L, RingA^(a), X¹, X^(2a), X³a, R¹, R^(z) and m are as described above.

As defined above and described herein, each of X¹, X^(2a), and X^(3a) isindependently a bivalent moiety selected from a covalent bond, —CH₂—,—C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X¹ is selected from those depicted in Table 1,below.

In some embodiments, X^(2a) is a covalent bond, —CH₂—, —C(O)—, —C(S)—,or

In some embodiments, X^(2a) is selected from those depicted in Table 1,below.

In some embodiments, X^(3a) is a covalent bond, —CH₂—, —C(O)—, —C(S)—,or

In some embodiments, X^(3a) is selected from those depicted in Table 1,below.

As defined above and described herein, each of X⁴ and X⁵ isindependently a bivalent moiety selected from —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(4a) is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(4a) is selected from those depicted in Table 1,below.

In some embodiments, X^(5a) is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(5a) is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, or an optionallysubstituted C₁₋₄ aliphatic.

In some embodiments, R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR,—S(O)R, —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each of R², R^(3b), and R^(4a) isindependently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or—N(R)S(O)₂R.

In some embodiments, R² is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R² is selected from those depicted in Table 1,below.

In some embodiments, R^(3b) is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R^(3b) is methyl.

In some embodiments, R^(3b) is selected from those depicted in Table 1,below.

In some embodiments, R^(4a) is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R^(4a) is methyl.

In some embodiments, R^(4a) is selected from those depicted in Table 1,below.

As defined above and described herein, R^(a) is hydrogen or C₁₋₆aliphatic.

In some embodiments, R^(1a) is t-butyl.

In some embodiments, R^(1a) is selected from those depicted in Table 1,below.

As defined above and described herein, each R⁶ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphaticgroup. In some embodiments, R⁶ is an optionally substituted phenyl. Insome embodiments, R⁶ is an optionally substituted 4-7 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁶ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R⁶ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A^(a) is a fused ringselected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to7-membered partially saturated carbocyclyl, 5 to 7-membered partiallysaturated heterocyclyl with 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments Ring A^(a) is a fused 6-membered aryl containing 0-2nitrogen atoms. In some embodiments Ring A^(a) is a fused 5 to7-membered partially saturated carbocyclyl. In some embodiments RingA^(a) is a fused 5 to 7-membered partially saturated heterocyclyl with1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.In some embodiments Ring A^(a) is a fused 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring A^(a) is a fused phenyl.

In some embodiments, Ring A^(a) is selected from those depicted in Table1, below.

As defined above and described herein, Ring B^(a) is selected from6-membered aryl containing 0-2 nitrogen atoms or a 8-10 memberedbicyclic heteroaryl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B^(a) is a 6-membered aryl containing 0-2nitrogen atoms. In some embodiments, Ring B^(a) is a 8-10 memberedbicyclic heteroaryl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B^(a) is

In some embodiments, Ring B^(a) is selected from those depicted in Table1, below.

As defined above and described herein, Ring C^(a) is selected from6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroarylwith 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, Ring C^(a) is a 6-membered aryl containing 0-2nitrogen atoms. In some embodiments, Ring C^(a) is a 5-memberedheteroaryl with 1-3 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, Ring C^(a) is

In some embodiments, Ring C^(a) is selected from those depicted in Table1, below.

As defined above and described herein, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments, m is selected from those depicted in Table 1,below.

In some embodiments, o is selected from those depicted in Table 1,below.

As defined above and described herein, o is 0, 1, 2, 3 or 4.

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2. In some embodiments, o is 3. In some embodiments, ois 4.

In some embodiments, o is selected from those depicted in Table 1,below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, qis 4.

In some embodiments, q is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are optionally taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is phenyl. Insome embodiments, R is a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, two R groups on thesame nitrogen are optionally taken together with their intervening atomsto form a 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-ab:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R₉, R₁₀, R₁₁, R_(14a), and R₁₅ is as described and definedin WO 2017/030814, WO 2016/118666, and US 2017/0327469, the entirety ofeach of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-ac-1 or I-ac-2:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables X, W³, W⁵, R₉, R₁₀, R₁₁, R_(14a), R_(14b), R₁₅, R₁₆, and ois as described and defined in WO 2017/030814, WO 2016/118666, and US2017/0327469, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an IAP binding moiety thereby forming acompound of formula I-ad:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables W, Y, Z, R¹, R², R³, R⁴, and R⁵ is as described anddefined in WO 2014/044622, US 2015/0225449. WO 2015/071393, and US2016/0272596, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a MDM2 binding moiety thereby forming acompound of formula I-ae:

or a pharmaceutically acceptable salt thereof, as described and definedin Hines, J. et al., Cancer Res. (DOI: 10.1158/0008-5472.CAN-18-2918),the entirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a DCAF16 binding moiety thereby forming acompound of formula I-af:

or a pharmaceutically acceptable salt thereof, as described and definedin Zhang, X. et al., bioRxiv (doi: https://doi.org/10.1101/443804), theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF114 binding moiety thereby forming acompound of formula I-ag:

or a pharmaceutically acceptable salt thereof, as described and definedin Spradin, J. N. et al., bioRxiv (doi: https://doi.org/10.1101/436998),the entirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF4 binding moiety thereby forming acompound of formula I-ah:

or a pharmaceutically acceptable salt thereof, as described and definedin Ward, C. C., et al., bioRxiv (doi: https:://doi.org/10.1101/4391.25),the entirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-aay-1 or I-aay-2:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, X, and Y is as defined and described in WO2019/084026, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-aaz-1 or I-aaz-2:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R³, and Y is as defined and described in WO2019/084030, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-aaaa-1, I-aaaa-2,I-aaaa-3, or I-aaaa-4:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described herein, and wherein each of the variablesR⁴, R¹⁰, R¹¹, R¹⁵, R¹⁶, R⁷, W¹, W², and X is as defined in WO2019/099868 which is herein incorporated by reference in its entirety,and wherein

is attached to R¹⁷ or R¹⁶ at the site of attachment of R¹² as defined inWO 2018/237026, such that

takes the place of the R¹² substituent.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula formula I-bbbb:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, wherein:

-   each X¹ is independently —CH₂—, —O—, —NR—, —CF₂—,

—C(O)—, —C(S)—, or

-   X² and X³ are independently —CH₂—, —C(O)—, —C(S)—, or

-   Z¹ and Z² are independently a carbon atom or a nitrogen atom;-   Ring A^(x) is a fused ring selected from benzo or a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   L^(x) is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—, —NR—, or —S(O)₂—;-   each R^(x) is independently selected from hydrogen, deuterium,    R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂,    —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,    —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃; or    -   two R^(x) groups are optionally taken together to form an        optionally substituted 5-8 membered partially unsaturated or        aryl fused ring having 0-2 heteroatoms independently selected        from nitrogen, oxygen, or sulfur;-   each R is independently selected from hydrogen, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-7 membered saturated, partially unsaturated, or        heteroaryl ring having 0-3 heteroatoms, in addition to the        carbon or nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   R is selected from

or hydrogen;

-   Ring B^(x) is phenyl, a 4-10 membered saturated or partially    unsaturated mono- or bicyclic carbocyclic or heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, wherein    Ring B^(x) is further optionally substituted with 1-2 oxo groups;-   each R^(w) is independently selected from hydrogen, deuterium,    R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂,    —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,    —OP(O)(NR₂)₂, and —SiR₃;-   each R^(z) is independently selected from an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated    or partially unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   is a single or double bond;-   x is 0, 1, 2, 3 or 4;-   y is 0, 1 or 2; and-   w is 0, 1, 2, 3 or 4.

As defined above and described herein, each X¹ is independently —CH₂—,—O—, —NR—, —CF₂—,

—C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CH₂—. In some embodiments, X¹ is —O—. In some embodiments, X¹ is —NR—.In some embodiments, X¹ is —CF₂—. In some embodiments, X is

In some embodiments, X is —C(O)—. In some embodiments, X is —C(S)—. Insome embodiments, X¹ is

In certain embodiments, X¹ is selected from those shown in the compoundsof Table 1.

As defined above and described herein, X² and X³ are independently—CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X² and X³ are independently —CH₂—. In someembodiments, X² and X³ are independently —C(O)—. In some embodiments, X²and X³ are independently —C(S)—. In some embodiments, X² and X³ areindependently

In certain embodiments, X² and X³ are independently selected from thoseshown in the compounds of Table 1.

As define above and described herein, Z¹ and Z² are independently acarbon atom or a nitrogen atom.

In some embodiments, Z¹ and Z² are independently a carbon atom. In someembodiments, Z¹ and Z² are independently a carbon atom.

In certain embodiments, Z¹ and Z² are independently selected from thoseshown in the compounds of Table 1.

As defined above and described herein, Ring A^(x) is fused ring selectedfrom benzo or a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring A^(x) is benzo. In some embodiments, RingA^(x) is a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring A^(x) is

In some embodiments, Ring A^(x) is

In some embodiments, Ring A^(x) is

In some embodiments, Ring A^(x) is

In certain embodiments, Ring A^(x) is selected from those shown in thecompounds of Table 1.

As defined above and described herein, Lx is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, or —S(O)₂—.

In some embodiments, LU is a covalent bond. In some embodiments, LU is aC₁₋₃ bivalent straight or branched saturated or unsaturated hydrocarbonchain wherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, or —S(O)₂—.

In some embodiments, L^(x) is —C(O)—.

In certain embodiments, L^(x) is selected from those shown in thecompounds of Table 1.

As defined above and described herein, each R is independently selectedfrom hydrogen, deuterium, R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂,—OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃, or twoR^(x) groups are optionally taken together to form an optionallysubstituted 5-8 membered partially unsaturated or aryl fused ring having0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(x) is hydrogen. In some embodiments, R^(x) isdeuterium. In some embodiments, R^(x) is R^(z). In some embodiments,R^(x) is halogen. In some embodiments, R^(x) is —CN. In someembodiments, R^(x) is —NO₂. In some embodiments, R^(x) is —OR. In someembodiments, R^(x) is —SR. In some embodiments, R^(x) is —NR₂. In someembodiments, R^(x) is —S(O)₂R. In some embodiments, R^(x) is —S(O)₂NR₂.In some embodiments, R^(x) is —S(O)R. In some embodiments, R^(x) is—CF₂R. In some embodiments, R^(x) is —CF₃. In some embodiments, R^(x) is—CR₂(OR). In some embodiments, R^(x) is —CR₂(NR₂). In some embodiments,R^(x) is —C(O)R. In some embodiments, R^(x) is —C(O)OR. In someembodiments, R^(x) is —C(O)NR₂. In some embodiments, R^(x) is—C(O)N(R)OR. In some embodiments, R^(x) is —OC(O)R. In some embodiments,R^(x) is —OC(O)NR₂. In some embodiments, R^(x) is —C(S)NR₂. In someembodiments, R^(x) is —N(R)C(O)OR. In some embodiments, R^(x) is—N(R)C(O)R. In some embodiments, R^(x) is —N(R)C(O)NR₂. In someembodiments, R^(x) is —N(R)S(O)₂R. In some embodiments, R^(x) is—OP(O)R₂. In some embodiments, R^(x) is —OP(O)(OR)₂. In someembodiments, R^(x) is —OP(O)(OR)NR₂. In some embodiments, R^(x) is—OP(O)(NR₂)₂. In some embodiments, R^(x) is —Si(OR)R₂. In someembodiments, R^(x) is —SiR₃. In some embodiments, two R^(x) groups areoptionally taken together to form an optionally substituted 5-8 memberedpartially unsaturated or aryl fused ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(x) is fluoro. In some embodiments, R^(x) isbromo. In some embodiments, R^(x) is methyl. In some embodiments, R^(x)is —OH. In some embodiments, R^(x) is —NH₂. In some embodiments, R^(x)is —NHCH₃. In some embodiments, R^(x) is —N(CH₃)₂. In some embodiments,R^(x) is —NHCH(CH₃)₂. In some embodiments, R^(x) is —NHSO₂CH₃. In someembodiments, R^(x) is —CH₂OH. In some embodiments, R^(x) is —CH₂NH₂. Insome embodiments, R^(x) is —C(O)NH₂. In some embodiments, R^(x) is—C(O)NHCH₃. In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In certain embodiments, each R^(x) is independently selected from thoseshown in the compounds of Table 1.

As defined above and described here, each R is independently selectedfrom hydrogen, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or two R groups on the same carbon or nitrogen are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the carbon or nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted C₁₋₆ aliphatic. In some embodiments, R is anoptionally substituted phenyl. In some embodiments, R is an optionallysubstituted 4-7 membered saturated or partially unsaturated heterocyclichaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R is an optionally substituted a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, two R groups onthe same carbon or nitrogen are optionally taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the carbon or nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

As defined above and described herein, R^(y) is selected from

or hydrogen.

In some embodiment R^(y) is

In some embodiments, R^(y) is hydrogen.

In certain embodiments, R^(y) is selected from those shown in thecompounds of Table 1.

As defined above and described herein, Ring B^(x) is phenyl, a 4-10membered saturated or partially unsaturated mono- or bicycliccarbocyclic or heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, wherein Ring B^(x) is further optionally substitutedwith 1-2 oxo groups.

In some embodiments, Ring B^(x) is phenyl. In some embodiments, RingB^(x) is a 4-10 membered saturated or partially unsaturated mono- orbicyclic carbocyclic or heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur In someembodiments, Ring B^(x) is a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Ring B^(x) is further optionally substituted with 1-2oxo groups.

In some embodiments, Ring B^(x) is

In some embodiments, Ring B^(x) is

In some embodiments, Ring B^(x) is

In some embodiments, Ring B^(x) is

In some embodiments, Ring B^(x) is

In certain embodiments, Ring B^(x) is selected from those shown in thecompounds of Table 1.

As defined above and described herein, each R^(w) is independentlyselected from hydrogen, deuterium, R^(z), halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂),—C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂, and —SiR₃.

In some embodiments, R^(w) is hydrogen. In some embodiments, R^(w) isdeuterium. In some embodiments, R^(w) is R^(z). In some embodiments,R^(w) is halogen. In some embodiments, R^(w) is —CN. In someembodiments, R^(w) is —NO₂. In some embodiments, R^(w) is —OR. In someembodiments, R^(w) is —SR. In some embodiments, R^(w) is —NR₂. In someembodiments, R^(w) is —S(O)₂R. In some embodiments, R^(w) is —S(O)₂NR₂.In some embodiments, R^(w) is —S(O)R. In some embodiments, R^(w) is—CF₂R. In some embodiments, R^(w) is —CF₃. In some embodiments, R^(w) is—CR₂(OR). In some embodiments, R^(w) is —CR₂(NR₂). In some embodiments,R^(w) is —C(O)R. In some embodiments, R^(w) is —C(O)OR. In someembodiments, R^(w) is —C(O)NR₂. In some embodiments, R^(w) is—C(O)N(R)OR. In some embodiments, R^(w) is —OC(O)R. In some embodiments,R^(w) is —OC(O)NR₂. In some embodiments, R^(w) is —N(R)C(O)OR. In someembodiments, R^(w) is —N(R)C(O)R. In some embodiments, R^(w) is—N(R)C(O)NR₂. In some embodiments, R^(w) is —N(R)S(O)₂R. In someembodiments, R^(w) is —OP(O)R₂. In some embodiments, R^(w) is—OP(O)(OR)₂. In some embodiments, R^(w) is —OP(O)(OR)NR₂. In someembodiments, R^(w) is —OP(O)(NR₂)₂. In some embodiments, R^(w) is —SiR₃.

In certain embodiments, R^(w) is selected from those shown in thecompounds of Table 1.

As defined above and described herein, each R^(z) is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(z) is an optionally substituted C₁₋₆ aliphatic.In some embodiments, R^(z) is an optionally substituted phenyl. In someembodiments, R^(z) is an optionally substituted 4-7 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(z) is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In some embodiments, R^(z) is

In certain embodiments, R^(z) is selected from those shown in thecompounds of Table 1.

As defined above and described herein,

is a single or double bond.

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

In certain embodiments,

is selected from those shown in the compounds of Table 1.

As defined above and described herein, w is 0, 1, 2, 3 or 4.

In some embodiments, w is 0. In some embodiments, w is 1. In someembodiments, w is 2. In some embodiments, w is 3. In some embodiments, wis 4.

In certain embodiments, w is selected from those shown in the compoundsof Table 1.

As defined above and described herein, x is 0, 1, 2, 3 or 4.

In some embodiments, x is 0. In some embodiments, x is 1. In someembodiments, m is 2. In some embodiments, x is 3. In some embodiments, xis 4.

In certain embodiments, x is selected from those shown in the compoundsof Table 1.

As defined above and described herein, y is 0, 1 or 2.

In some embodiments, y is 0. In some embodiments, y is 1. In someembodiments, y is 2.

In certain embodiments, y is selected from those shown in the compoundsof Table 1.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is benzo, y is 1, X¹ is —CH₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-bbbb-1:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is imidazolyl, y is 1, X¹ is —CH₂—,X² and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, toprovide a compound of formula I-bbbb-2:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,LU, and R^(y) is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is imidazolyl, y is 1, X¹ is —CH₂—,X² and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, toprovide a compound of formula I-bbbb-3:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), and R^(y) is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is oxazolyl, y is 1, X¹ is —CH₂—, X²and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-bbbb-4:

or a pharmaceutically acceptable salt thereof, wherein each of STAT andL is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is benzo, y is 0, X² and X³ are—C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide a compoundof formula I-bbbb-5:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is benzo, y is 1, X¹ is —O—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-bbbb-6:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is benzo, y is 1, X¹ is —NR—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-bbbb-7:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R, R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is benzo, y is 1, X¹ is —CF₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-bbbb-8:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is benzo, y is 1, X¹ is

X² and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, toprovide a compound of formula I-bbbb-9:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is pyridyl, y is 1, X¹ is —CH₂—, X²and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-bbbb-10:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A^(x) is pyridyl, y is 1, X¹ is —CH₂—, X²and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-bbbb-11:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-bbbb, wherein Ring A is benzo, y is 1, X¹, X² and X³ are—C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide a compoundof formula I-bbbb-12:

or a pharmaceutically acceptable salt thereof, wherein each of STAT, L,L^(x), R^(x), R^(y), and x is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is selected from those in Table 1.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RPN13 binding moiety thereby forming acompound of formula I-cccc:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables A, Y, and Z is as described and defined in WO 2019/165229,the entirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a Ubr1 binding moiety as described inShanmugasundaram, K. et al, J. Bio. Chem. 2019, doi:10.1074/jbc.AC119.010790, the entirety of each of which is hereinincorporated by reference, thereby forming a compound of formulaI-dddd-1 or I-dddd-2:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a CRBN binding moiety thereby forming acompound of formula I-eeee:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R₁, R₂, R₃, R₄, R₅, Q, X, and n is as described anddefined in US 2019/276474, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moietythereby forming a compound of formula I-ffff-1, I-ffff-2, I-ffff-3 orI-ffff-4:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables Y, A¹, and A³ is as described and defined in WO2019/236483, the entirety of each of which is herein incorporated byreference.

Degradation Inducing Moiety (DIM)

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdescribed above and herein, and DIM is a degradation inducing moietyselected from LBM, a lysine mimetic, or a hydrogen atom.

In some embodiments, DIM is LBM as described above and herein. In someembodiments, DIM is a lysine mimetic. In some embodiments, the covalentattachment of ubiquitin to one or more members of the STAT proteinfamily (i.e., STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) isachieved through the action of a lysine mimetic. In some embodiments,upon the binding of a compound of formula II to STAT1, the moiety thatmimics a lysine undergoes ubiquitination thereby marking STAT1 fordegradation via the Ubiquitin-Proteasome Pathway (UPP). In someembodiments, upon the binding of a compound of formula II to STAT2, themoiety that mimics a lysine undergoes ubiquitination thereby markingSTAT2 for degradation via the Ubiquitin-Proteasome Pathway (UPP). Insome embodiments, upon the binding of a compound of formula II to STAT3,the moiety that mimics a lysine undergoes ubiquitination thereby markingSTAT3 for degradation via the Ubiquitin-Proteasome Pathway (UPP). Insome embodiments, upon the binding of a compound of formula II to STAT4,the moiety that mimics a lysine undergoes ubiquitination thereby markingSTAT4 for degradation via the Ubiquitin-Proteasome Pathway (UPP). Insome embodiments, upon the binding of a compound of formula II toSTAT5A, the moiety that mimics a lysine undergoes ubiquitination therebymarking STAT5A for degradation via the Ubiquitin-Proteasome Pathway(UPP). In some embodiments, upon the binding of a compound of formula IIto STAT5B, the moiety that mimics a lysine undergoes ubiquitinationthereby marking STAT5B for degradation via the Ubiquitin-ProteasomePathway (UPP). In some embodiments, upon the binding of a compound offormula II to STAT6, the moiety that mimics a lysine undergoesubiquitination thereby marking STAT6 for degradation via theUbiquitin-Proteasome Pathway (UPP).

In some embodiments, DIM is

In some embodiments, DIM is

In some embodiments, DIM is

In some embodiments, DIM is selected from those depicted in Table 1A,below.

In some embodiments, the present invention provides the compound offormula I as a compound of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein each of STAT andL is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides the compound offormula I as a compound of formula II-b:

or a pharmaceutically acceptable salt thereof, wherein each of STAT andL is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides the compound offormula I as a compound of formula II-c:

or a pharmaceutically acceptable salt thereof, wherein each of STAT andL is as defined above and described in embodiments herein, both singlyand in combination.

In certain embodiments, the present invention provides a compound ofFormula II, wherein DIM is a lysine mimetic

thereby forming a compound of Formulae II-d-1, II-d-2, or II-d-3,respectively:

or a pharmaceutically acceptable salt thereof, wherein L and STAT are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R⁴, R⁵, A, B, E, Y, Y′, Z, Z′, and k are as definedand described in U.S. Pat. No. 7,622,496, the entirety of each of whichis herein incorporated by reference.

Hydrogen Atom

In some embodiments, DIM is a hydrogen atom. In some embodiments, thecovalent attachment of ubiquitin to one or more members of the STATprotein family (i.e., STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6) is achieved through a provided compound wherein DIM is a hydrogenatom. In some embodiments, upon the binding of a compound of formula IIto STAT1, the moiety being hydrogen effectuates ubiquitination therebymarking STAT1 for degradation via the Ubiquitin-Proteasome Pathway(UPP). In some embodiments, upon the binding of a compound of formula IIto STAT2, the moiety being hydrogen effectuates ubiquitination therebymarking STAT2 for degradation via the Ubiquitin-Proteasome Pathway(UPP). In some embodiments, upon the binding of a compound of formula IIto STAT3, the moiety being hydrogen effectuates ubiquitination therebymarking STAT3 for degradation via the Ubiquitin-Proteasome Pathway(UPP). In some embodiments, upon the binding of a compound of formula IIto STAT4, the moiety being hydrogen effectuates ubiquitination therebymarking STAT4 for degradation via the Ubiquitin-Proteasome Pathway(UPP). In some embodiments, upon the binding of a compound of formula IIto STAT5A, the moiety being hydrogen effectuates ubiquitination therebymarking STAT5A for degradation via the Ubiquitin-Proteasome Pathway(UPP). In some embodiments, upon the binding of a compound of formula IIto STAT5B, the moiety being hydrogen effectuates ubiquitination therebymarking STAT5B for degradation via the Ubiquitin-Proteasome Pathway(UPP). In some embodiments, upon the binding of a compound of formula IIto STAT6, the moiety being hydrogen effectuates ubiquitination therebymarking STAT6 for degradation via the Ubiquitin-Proteasome Pathway(UPP).

In some embodiments, DIM is selected from those depicted in Table 1A,below.

In some embodiments, the present invention provides the compound offormula II wherein DIM is a hydrogen atom, thereby forming a compound offormula II-d-4:

or a pharmaceutically acceptable salt thereof, wherein each of STAT andL is as defined above and described in embodiments herein, both singlyand in combination.

STAT Binding Moiety (STAT)

As defined above and described herein, STAT is a STAT binding moietycapable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6.

In some embodiments, STAT is a STAT binding moiety capable of binding toSTAT1. In some embodiments, STAT is a STAT binding moiety capable ofbinding to STAT2. In some embodiments, STAT is a STAT binding moietycapable of binding to STAT3. In some embodiments, STAT is a STAT bindingmoiety capable of binding to STAT4. In some embodiments, STAT is a STATbinding moiety capable of binding to STAT5A. In some embodiments, STATis a STAT binding moiety capable of binding to STAT5B. In someembodiments, STAT is a STAT binding moiety capable of binding to orSTAT6.

As defined herein and described below, wherein a formula is depictedusing square brackets, e.g.,

L is attached to a modifiable carbon, oxygen, or nitrogen atom withinSTAT including substitution or replacement of a defined group in STAT.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-ai or II-e:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₄, R₅, and R₆ is as described anddefined in US 2004/0138189, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aj or II-f:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₀, R₂, R₃, and R₄ is as described and defined inUS 2005/0277680, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-ak or II-g:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₆, AA, and n is as described anddefined in US 2008/0139456, the entirety of each of which is hereinincorporated by reference.

In some embodiments, the invention provides a compound of formula I orformula II, wherein STAT is a STAT3 binding moiety selected from acompound recited in US 2006/0247318 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein or is attached toa modifiable carbon or oxygen atom.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-a1 or II-i:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereinthe one or more amino acids that have been replaced with a structuralanalog is as described and defined in US 2007/0010428, the entirety ofeach of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-am or II-j:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables A, B, Z, n, and m is as described and defined inWO 2007/042912 and U.S. Pat. No. 7,786,142, the entirety of each ofwhich is herein incorporated by reference.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in WO 2007/136858 such as, for example S31-201(shown in FIG. 7 ), NSC-59263 (shown in FIG. 8 ), NSC-42067 (shown inFIG. 9 ), Formula A (shown in FIG. 10 ), Formula B (shown in FIG. 11 ),Formula C (shown in FIG. 12A), Formula D (FIG. 12B), Formula E (FIG.12C), Formula F (FIG. 12D), NSC 75912 (shown in FIG. 50 ), NSC 11421(shown in FIG. 49 ), NSC 91529 (shown in FIG. 51 ), NSC 263435 (shown inFIG. 48 ), HL2-006-1 (shown in FIG. 13 ), HL2-006-2 (shown in FIG. 14 ),HL2-006-3 (shown in FIG. 15 ), HL2-006-4 (shown in FIG. 16 ), HL2-006-5(shown in FIG. 17 ), HL2-011-1 (shown in FIG. 18 ), HL2-011-2 (shown inFIG. 19 ), HL2-01 1-3 (shown in FIG. 20 ), HL2-01 1-4 (shown in FIG. 21), HL2-011-5 (shown in FIG. 22 ), BG2069-1 (shown in FIG. 23 ),HL2-011-6 (shown in FIG. 24 ), HL2-011-7 (shown in FIG. 25 ), HL2-005(shown in FIG. 26 ), HL2-003 (shown in FIG. 27 ), BG2066 (shown in FIG.28 ), BG2074 (shown in FIG. 29 ), BG3004 (shown in FIG. 30 ), BG3006A(shown in FIG. 31 ), BG3006B (shown in FIG. 32 ), BG3006D (shown in FIG.33 ), BG3009 (shown in FIG. 34 ), RPM381 (shown in FIG. 35 ), RPM384(shown in FIG. 35 ), RPM385 (shown in FIG. 35 ), RPM405 (shown in FIG.36 ), RPM411 (shown in FIG. 36 ), RPM407 (shown in FIG. 37 ), RPM412(shown in FIG. 37 ), RPM408 (shown in FIG. 38 ), RPM410 (shown in FIG.38 ), RPM415 (shown in FIG. 39 ), RPM416 (shown in FIG. 39 ), RPM418(shown in FIG. 40 ), RPM418-A (shown in FIG. 40 ), RPM427 (shown in FIG.41 ), RPM431 (shown in FIG. 42 ), RPM432 (shown in FIG. 43 ), RPM444(shown in FIG. 44 ) RPM448 (shown in FIG. 44 ), RPM445 (shown in FIG. 45), RPM447 (shown in FIG. 45 ), RPM452 (shown in FIG. 46 ), and RPM202,or a pharmaceutically acceptable salt thereof, wherein

or is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 or STAT5 binding moietythereby forming a compound of formula I-an or II-k:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, X, and Z is as described and defined inU.S. Pat. No. 7,960,434, the entirety of each of which is hereinincorporated by reference.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in US 2006/0247318 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon, nitrogen, or oxygen atom.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 or STAT5 binding moietythereby forming a compound of formula I-ap or II-m:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², A, X₁, and Y is as described and definedin U.S. Pat. No. 8,263,599, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aq or II-n:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R^(1′), R², R³, R⁶, AA, and n is as describedand defined in WO 2008/067270, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT1, STAT3 or STAT5 bindingmoiety thereby forming a compound of formula I-ar-1, I-ar-2, I-ar-3,I-ar-4, II-o-1, II-o-2, II-o-3, or II-o-4:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R, R¹, R², R³, R^(3a), R^(3b), R⁴, x, and y is asdescribed and defined in WO 2008/156644 and US 2011/0144043, theentirety of each of which is herein incorporated by reference.

In some embodiments, the present invention provides a compounds offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in WO 2009/032338 such as, for example apratoxinA, apratoxin B, apratoxin C, E-dehydroapratoxin A, apratoxin D,apratoxin E, and described analogs thereof, or a pharmaceuticallyacceptable salt thereof, wherein

is attached to a modifiable carbon, nitrogen, or oxygen atom.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-as or II-p:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², R³, R⁴, R⁵, R⁶, R⁷, W, and X is asdescribed and defined in WO 2010/004761 and U.S. Pat. No. 8,446,290, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-at or II-q:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables Ro, R2, R3, R4, and n is as described and definedin WO 2010/005807 and U.S. Pat. No. 8,143,412, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-au or II-r:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², R³, R⁴, X, and Y is as described anddefined in WO 2010/077589 and US 2011/0319362, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula II, wherein STAT is a STAT3 binding moiety thereby forming acompound of formula II-r′-1, II-r′-2, II-r′-3, or II-r′-4:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are asdefined above and described in embodiments herein, and wherein:

-   Ring M is an optionally substituted ring selected from phenyl,    naphthyl, a 5 to 10-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 5 to    11-membered saturated or partially unsaturated carbocyclyl, and a 5    to 11-membered saturated or partially unsaturated heterocyclyl with    1-4 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur;-   each R^(x) and R^(y) is independently hydrogen, RA, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R,    —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂, —C(S)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, —N⁺(O⁻)R₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —P(O)R₂, —SiR₃, —SF₅, —Si(OR)R₂, or

-   each R^(A) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form a 4-7 membered        saturated, partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the carbon or nitrogen,        independently selected from nitrogen, oxygen, and sulfur; and        each of the variables R³, R⁴, R^(a), Q, X, X′, Y, and Y′ is as        described and defined in WO 2010/077589 and US 2011/0319362, the        entirety of each of which is herein incorporated by reference.

In some embodiments, R^(x) is hydrogen. In some embodiments, R^(x) ismethanesulfonyl. In some embodiments, R^(x) is isopropyl. In someembodiments, R^(x) is isobutyl.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-av or II-s:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², R³, Z, X, and Y is as described anddefined in WO 2010/118309 and U.S. Pat. No. 8,841,257, the entirety ofeach of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula II, wherein STAT is a STAT3 binding moiety thereby forming acompound of formula II-s′-1, II-s′-2, or II-s′-3:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, Z, X, and Y is as described and defined in WO2010/118309 and U.S. Pat. No. 8,841,257, the entirety of each of whichis herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula II-r″:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are asdefined above and described in embodiments herein, and wherein:

-   L^(1′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L¹ are independently replaced by —O—, —NR—,    —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-11 membered saturated or partially unsaturated        monocyclic, bicyclic, bridged bicyclic, or spirocyclic        carbocyclic or heterocyclic ring having 1-3 heteroatoms, in        addition to the carbon or nitrogen from which the two R groups        are attached, independently selected from nitrogen, oxygen, and        sulfur;-   X′ is an optionally substituted —(CH₂)_(x)—, wherein 1-2 methylenes    of X′ is optionally replaced with a bivalent group selected from    —NR—, —N(COR)—, —N(CO₂R)—, —N(SO₂R)—, —N(CONR₂)—, and —N(SO₂NR₂)—,    -   wherein:    -   x is 1, 2, 3, 4, or 5;-   Y′ is an optionally substituted —(CH₂)_(y)—, wherein:    -   y is 1, 2, or 3;-   R^(3′) is hydrogen or R^(A);-   each R^(A) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   Ring M′ is an optionally substituted bivalent ring selected from    phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-11 membered saturated or partially unsaturated    carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Q′ is a bivalent moiety selected from —O—, —CR₂—, —CF₂—, —CFR—,    —C(O)—, —OCR₂—, and —C(S)—;-   R^(a1) and R^(a2) are each independently hydrogen or R^(A);-   Ring Z′ is a bivalent ring selected from phenylenyl, a 4-7 membered    saturated or partially unsaturated carbocyclylenyl or    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   R^(z′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   z is 0, 1, 2, 3, or 4; and-   n is 0 or 1.

In certain embodiments, the present invention provides a compound offormula II-r″-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(4′), X^(5′), and X^(6′) are each independently a bivalent moiety    selected from a covalent bond, —CR₂—, —C(O)—, —C(S)—, —O—, —S(O)—,    —S(O)₂—,

-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-11 membered saturated or partially unsaturated        monocyclic, bicyclic, bridged bicyclic, or spirocyclic        carbocyclic or heterocyclic ring having 1-3 heteroatoms, in        addition to the carbon or nitrogen from which the two R groups        are attached, independently selected from nitrogen, oxygen, and        sulfur;-   R^(6′) is hydrogen or R^(A);-   each R^(A) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   Ring D′ is selected from phenyl, a 4-11 membered saturated or    partially unsaturated monocyclic, bicyclic, bridged bicyclic, or    spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   R^(7′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)NROR,    —OC(O)R, —OC(O)NR₂, —NRC(O)OR, —NRC(O)R, —NRC(O)NR₂, or —NRS(O)₂R;-   p is 0, 1, 2, 3, or 4;-   L is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₂₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by -Cy-, —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, —S(O)₂—, —SiR₂—, —Si(OH)R—,    —Si(OH)₂—, —P(O)OR—, —P(O)R—, or —P(O)NR₂—, wherein:-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-11    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   L^(1′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L¹ are independently replaced by —O—, —NR—,    —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-;-   X¹ is an optionally substituted —(CH₂)_(x)—, wherein 1-2 methylenes    of X¹ is optionally replaced with a bivalent group selected from    —NR—, —N(COR)—, —N(CO₂R)—, —N(SO₂R)—, —N(CONR₂)—, and —N(SO₂NR₂)—,    -   wherein:    -   x is 1, 2, 3, 4, or 5;-   Y′ is an optionally substituted —(CH₂)_(y)—, wherein:    -   y is 1, 2, or 3;-   R^(3′) is hydrogen or R^(A);-   Ring M′ is an optionally substituted bivalent ring selected from    phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-11 membered saturated or partially unsaturated    carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Q′ is a bivalent moiety selected from —O—, —CR₂—, —CF₂—, —CFR—,    —C(O)—, —OCR₂—, and —C(S)—;-   R^(a1) and R^(a2) are each independently hydrogen or R^(A);-   Ring Z′ is a bivalent ring selected from phenylenyl, a 4-7 membered    saturated or partially unsaturated carbocyclylenyl or    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   R^(z′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   z is 0, 1, 2, 3, or 4; and-   n is 0 or 1.

In some embodiments, the present invention provides a compound offormula II-r″-1, wherein Ring D′ is phenyl, p is 1,

n is 1, and Q′ is —C(O)— as shown, to provide a compound of formulaII-r″-2:

or a pharmaceutically acceptable salt thereof, wherein each of X^(4′),X^(5′), X^(6′), R^(3′), R^(6′), L, L^(1′), Ring M′, Ring Z′, X′, Y′,R^(a1), R^(a2), R^(z′), and z is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-1, wherein Ring D′ is phenyl, p is 1,

R^(3′) is

n is 1, and X^(4′), X^(5′), and Q′ are —C(O)— as shown, to provide acompound of formula II-r″-3:

or a pharmaceutically acceptable salt thereof, wherein each of X^(6′),R^(6′), L, L^(1′), Ring M′, Ring Z′, X′, Y′, R^(a1), R^(a2), R^(z′), andz is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula II-r″-1, wherein Ring D′ is phenyl, p is 1, R^(7′) is

X¹ is

Y′ is

n is 1, and X^(4′), X^(5′), and Q′ are —C(O)— as shown, to provide acompound of formula II-r″-4:

or a pharmaceutically acceptable salt thereof, wherein each of X^(6′),R^(3′), R^(6′), L, L^(1′), Ring M′, Ring Z′, R^(a1), R^(a2), R^(z′), andz is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula II-r″-1, wherein Ring D′ is phenyl, p is 1, R^(7′) is

n is 1, Ring M′ is

and X^(4′), X^(5′), and Q′ are —C(O)— as shown, to provide a compound offormula II-r″-5:

or a pharmaceutically acceptable salt thereof, wherein each of X^(4′),X^(5′), X^(6′), R^(3′), R^(6′), L, L^(1′), Ring Z′, X′, Y′, R^(a1),R^(a2), R^(z′), and z is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-1, wherein Ring D′ is phenyl, p is 1,

n is 1, L^(1′) is

Ring Z′ is phenylenyl, and X^(4′), X^(5′), and Q′ are —C(O)— as shown,to provide a compound of formula II-r″-6:

or a pharmaceutically acceptable salt thereof, wherein each of X^(4′),X^(5′), X^(6′), R_(3′), R^(6′), L, Ring M′, X′, Y′, R^(a1), R^(a2),R^(z′), and z is as defined above and described in embodiments herein,both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II-r″-7:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are asdefined above and described in embodiments herein, and wherein:

-   L^(1′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L^(1′) are independently replaced by —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-;-   L^(2′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L^(2′) are independently replaced by —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-11 membered saturated or partially unsaturated        monocyclic, bicyclic, bridged bicyclic, or spirocyclic        carbocyclic or heterocyclic ring having 1-3 heteroatoms, in        addition to the carbon or nitrogen from which the two R groups        are attached, independently selected from nitrogen, oxygen, and        sulfur;-   R^(3′) is hydrogen or R^(A);-   each R^(A) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   Ring M′ is an optionally substituted bivalent ring selected from    phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-11 membered saturated or partially unsaturated    carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Q′ is a bivalent moiety selected from —O—, —CR₂—, —CF₂—, —CFR—,    —C(O)—, —OCR₂—, and —C(S)—; R^(a1) and R^(a2) are each independently    hydrogen or R^(A);-   Y′ is an optionally substituted —(CH₂)_(y)—, wherein:    -   y is 1, 2, or 3;-   Ring W′ is an optionally substituted ring selected from a 5-9    membered saturated or partially unsaturated heterocyclyl;-   Ring U′ is a ring selected from phenyl, a 5-6 membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, and a 5-7 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R^(u′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   u is 0, 1, 2, 3, or 4;-   Ring Z′ is a bivalent ring selected from phenylenyl, a 4-7 membered    saturated or partially unsaturated carbocyclylenyl or    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   R^(z′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   z is 0, 1, 2, 3, or 4; and-   n is 0 or 1.

In certain embodiments, the present invention provides a compound offormula II-r″-8:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CR₂—,    —C(O)—, —C(S)—, —CR(CF₃)—, —P(O)OR—, —P(O)R—, —P(O)NR₂—, —S(O)—,    —S(O)₂—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —SiR₂—;-   R¹ is hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂,    —P(O)(OR)₂, —P(O)NR₂OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)R₂, —SiR₃, or    an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-11 membered saturated or partially unsaturated        monocyclic, bicyclic, bridged bicyclic, or spirocyclic        carbocyclic or heterocyclic ring having 1-3 heteroatoms, in        addition to the carbon or nitrogen from which the two R groups        are attached, independently selected from nitrogen, oxygen, and        sulfur;-   each R² is independently hydrogen, R^(A), halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)NR₂, —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂,    —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR,    —NRC(O)R, —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂,    —NRP(O)(OR)NR₂, —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   each R^(A) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic or tricyclic ring selected from

wherein:

-   Ring B is a fused ring selected from benzo, 5-6 membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, and a 5 to 7-membered saturated or partially    unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —NR₂, or —SR;-   each R⁴ is independently hydrogen, R^(A), halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —OC(O)R, —OC(O)NR₂, —NRC(O)OR, —NRC(O)R, —NRC(O)NR₂, or    —NRS(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   m is 0, 1, 2, 3 or 4;-   L is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₂₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by -Cy-, —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, —S(O)₂—, —SiR₂—, —Si(OH)R—,    —Si(OH)₂—, —P(O)OR—, —P(O)R—, or —P(O)NR₂—, wherein:-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-11    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   L^(1′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L^(1′) are independently replaced by —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-;-   L^(2′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L^(2′) are independently replaced by —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-; R^(3′) is    hydrogen or R^(A);-   Ring M′ is an optionally substituted bivalent ring selected from    phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-11 membered saturated or partially unsaturated    carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Q′ is a bivalent moiety selected from —O—, —CR₂—, —CF₂—, —CFR—,    —C(O)—, —OCR₂—, and —C(S)—;-   R^(a1) and R^(a2) are each independently hydrogen or R^(A);-   Y′ is an optionally substituted —(CH₂)_(y)—, wherein:    -   y is 1, 2, or 3;-   Ring W′ is an optionally substituted ring selected from a 5-9    membered saturated or partially unsaturated heterocyclyl;-   Ring U′ is a ring selected from phenyl, a 5-6 membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, and a 5-7 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R^(u′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   u is 0, 1, 2, 3, or 4;-   Ring Z′ is a bivalent ring selected from phenylenyl, a 4-7 membered    saturated or partially unsaturated carbocyclylenyl or    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   R^(z′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   z is 0, 1, 2, 3, or 4; and-   n is 0 or 1.

In some embodiments, the present invention provides a compound offormula II-r″-8, wherein X¹, X², X³, R¹, and Ring A is

n is 1, Y′ is

Ring W′ is an 8-membered heterocyclyl, and Q′ is —C(O)— as shown, toprovide a compound of formula II-r″-9:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L¹, L^(2′), Ring M′, Ring U′, Ring Z′, R^(3′), R^(a1), R^(a2), R^(u′),u, R^(z′), and z is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-8, wherein X¹, X², X³, R¹, and Ring A is

n is 1, Y′ is

Ring W′ is an 8-membered heterocyclyl, Ring M′ is

and Q′ is —C(O)— as shown, to provide a compound of formula II-r″-10:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), L^(2′), Ring U′, Ring Z′, R^(3′), R^(a1), R^(a2), R^(u′), u,R^(z′), and z is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-8, wherein X¹, X², X³, R¹, and Ring A is

n is 1, Y′ is

Ring W′ is an 8-membered heterocyclyl, L^(2′) is

Ring U′ is phenyl, and Q′ is —C(O)— as shown, to provide a compound offormula II-r″-11:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), Ring M′, Ring Z′, R^(3′), R^(a1), R^(a2), R^(u′), u, R^(z′), andz is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula II-r″-8, wherein X¹, X², X³, R¹, and Ring A is

n is 1, Y′ is

Ring W′ is an 8-membered heterocyclyl, L^(1′) is

Ring Z′ is cyclohexyl, z is 0, and Q′ is —C(O)— as shown, to provide acompound of formula II-r″-12:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(2′), Ring M′, Ring U′, R^(3′), R^(a1), R^(a2), R^(u′), and u is asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula II-s″:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are asdefined above and described in embodiments herein, and wherein:

-   L^(2′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L^(2′) are independently replaced by —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-11 membered saturated or partially unsaturated        monocyclic, bicyclic, bridged bicyclic, or spirocyclic        carbocyclic or heterocyclic ring having 1-3 heteroatoms, in        addition to the carbon or nitrogen from which the two R groups        are attached, independently selected from nitrogen, oxygen, and        sulfur;-   R^(3′) is hydrogen or R^(A).-   each R^(A) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   Ring M′ is an optionally substituted bivalent ring selected from    phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-11 membered saturated or partially unsaturated    carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; Q′ is a    bivalent moiety selected from —O—, —CR₂—, —CF₂—, —CFR—, —C(O)—,    —OCR₂—, and —C(S)—;-   R^(a1) and R^(a2) are each independently hydrogen or R^(A);-   Ring V′ is an optionally substituted fused ring selected from a    6-membered aryl, a 5-6 membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    and a 5-7 membered saturated or partially unsaturated carbocyclyl or    heterocyclyl with 1-3 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   X¹ is an optionally substituted —(CH₂)_(x)—, wherein:    -   x is 0, 1, 2, or 3;-   Y′ is an optionally substituted —(CH₂)_(y)—, wherein:    -   y is 0, 1, 2, or 3;-   Ring U′ is a ring selected from phenyl, a 5-6 membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, and a 5-7 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R^(u′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R; and-   u is 0, 1, 2, 3, or 4.

In certain embodiments, the present invention provides a compound offormula II-s″-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CR₂—,    —C(O)—, —C(S)—, —CR(CF₃)—, —P(O)OR—, —P(O)R—, —P(O)NR₂—, —S(O)—,    —S(O)₂—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —SiR₂—;-   R¹ is hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂,    —P(O)(OR)₂, —P(O)NR₂OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)R₂, —SiR₃, or    an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-11 membered saturated or partially unsaturated        monocyclic, bicyclic, bridged bicyclic, or spirocyclic        carbocyclic or heterocyclic ring having 1-3 heteroatoms, in        addition to the carbon or nitrogen from which the two R groups        are attached, independently selected from nitrogen, oxygen, and        sulfur;-   each R² is independently hydrogen, R^(A), halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,    —C(O)NR₂, —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂,    —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR,    —NRC(O)R, —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂,    —NRP(O)(OR)NR₂, —NRP(O)(NR₂)₂, or —NRS(O)₂R;-   each R^(A) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   Ring A is a bicyclic or tricyclic ring selected from

wherein:

-   Ring B is a fused ring selected from benzo, 5-6 membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, and a 5 to 7-membered saturated or partially    unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —NR₂, or —SR;-   each R⁴ is independently hydrogen, R^(A), halogen, —CN, —NO₂, —OR,    —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —OC(O)R, —OC(O)NR₂, —NRC(O)OR, —NRC(O)R, —NRC(O)NR₂, or    —NRS(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   m is 0, 1, 2, 3 or 4;-   L is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₂₀ hydrocarbon chain, wherein    0-6 methylene units of L are independently replaced by -Cy-, —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, —S(O)₂—, —SiR₂—, —Si(OH)R—,    —Si(OH)₂—, —P(O)OR—, —P(O)R—, or —P(O)NR₂—, wherein:-   each -Cy- is independently an optionally substituted bivalent ring    selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7    membered saturated or partially unsaturated carbocyclylenyl, a 4-11    membered saturated or partially unsaturated spiro carbocyclylenyl,    an 8-10 membered bicyclic saturated or partially unsaturated    carbocyclylenyl, a 4-7 membered saturated or partially unsaturated    heterocyclylenyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially    unsaturated spiro heterocyclylenyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, an 8-10    membered bicyclic saturated or partially unsaturated    heterocyclylenyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    L^(2′) is a covalent bond or a bivalent, saturated or partially    unsaturated, straight or branched C₁₋₅ hydrocarbon chain, wherein    0-3 methylene units of L^(2′) are independently replaced by —O—,    —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—, or —S(O)₂-;-   R^(3′) is hydrogen or R^(A);-   Ring M′ is an optionally substituted bivalent ring selected from    phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 5-11 membered saturated or partially unsaturated    carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Q′ is a bivalent moiety selected from —O—, —CR₂—, —CF₂—, —CFR—,    —C(O)—, —OCR₂—, and —C(S)—;-   R^(a1) and R^(a2) are each independently hydrogen or R^(A);-   Ring V′ is an optionally substituted fused ring selected from a    6-membered aryl, a 5-6 membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    and a 5-7 membered saturated or partially unsaturated carbocyclyl or    heterocyclyl with 1-3 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   X′ is an optionally substituted —(CH₂)_(x)—, wherein:    -   x is 0, 1, 2, or 3;-   Y′ is an optionally substituted —(CH₂)_(y)—, wherein: y is 0, 1, 2,    or 3;-   Ring U′ is a ring selected from phenyl, a 5-6 membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, and a 5-7 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R^(u′) is hydrogen, R^(A), halogen, —CN, —NO₂, —OR, —SR, —NR₂,    —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —NRC(O)OR, —NRC(O)R,    —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂, —NRP(O)(OR)NR₂,    —NRP(O)(NR₂)₂, or —NRS(O)₂R; and-   u is 0, 1, 2, 3, or 4;

In some embodiments, the present invention provides a compound offormula II-s″-1, wherein X¹, X², X³, R¹, and Ring A is

n is 1, X¹ is

Y′ is —CH₂—, Ring V′ is a 6-member aryl, and Q′ is —C(O)— as shown, toprovide a compound of formula II-s″-2:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(2′), Ring M′, Ring U′, R_(3′), R^(a1), R^(a2), R^(u′), and u is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″-1, wherein X¹, X², X³, R¹, and Ring A is

n is 1, Ring M′ is

X′ is

Y′ is —CH₂—, Ring V′ is a 6-member aryl, and Q′ is —C(O)— as shown, toprovide a compound of formula II-s″-3:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(2′), Ring U′, R^(3′), R^(a1), R^(a2), R^(u′), and u is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″-1, wherein X¹, X², X³, R and Ring A is

n is 1, L^(2′) is

Ring U′ is phenyl, X′ is

Y′ is —CH₂—, Ring V′ is a 6-member aryl, and Q′ is —C(O)— as shown, toprovide a compound of formula II-s″-4:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,Ring M′, R^(3′), R^(a1), R^(a2), R^(u′), and u is as defined above anddescribed in embodiments herein, both singly and in combination.

As defined above and described herein, X^(4′), X^(5′), and X^(6′) areeach independently a bivalent moiety selected from a covalent bond,—CR₂—, —C(O)—, —C(S)—, —O—, —S(O)—, —S(O)₂—,

In some embodiments, X^(4′) is a covalent bond. In some embodiments,X^(4′) is —CR₂—. In some embodiments, X⁴ is —C(O)—. In some embodiments,X^(4′) is —C(S)—. In some embodiments, X^(4′) is —O—. In someembodiments, X^(4′) is —S(O)—. In some embodiments, X^(4′) is —S(O)₂—.In some embodiments, X^(4′) is

In some embodiments, X^(4′) is

In some embodiments, X^(5′) is a covalent bond. In some embodiments,X^(5′) is —CR₂—. In some embodiments, X^(5′) is —C(O)—. In someembodiments, X^(5′) is —C(S)—. In some embodiments, X^(5′) is —O—. Insome embodiments, X^(5′) is —S(O)—. In some embodiments, X^(5′) is—S(O)₂—. In some embodiments, X^(5′) is

In some embodiments, X^(5′) is

In some embodiments, X^(6′) is a covalent bond. In some embodiments,X^(6′) is —CR₂—. In some embodiments, X^(6′) is —C(O)—. In someembodiments, X^(6′) is —C(S)—. In some embodiments, X^(6′) is —O—. Insome embodiments, X^(6′) is —S(O)—. In some embodiments, X^(6′) is—S(O)₂—. In some embodiments, X^(6′) is

In some embodiments, X^(6′) is

In some embodiments, X^(6′) is

In some embodiments, X is

As defined above and described herein, each R^(A) is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated carbocyclic or heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(A) is an optionally substituted C₁₋₆ aliphatic.In some embodiments, R^(A) is an optionally substituted phenyl. In someembodiments, R^(A) is an optionally substituted 4-7 membered saturatedor partially unsaturated carbocyclic or heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(A) is an optionally substituted 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R^(A) is

In some embodiments, R^(A) is —CH₂CO₂R. In some embodiments, R^(A) is—CH₂OCO₂R. In some embodiments, R^(A) is —CH₂C(O)NR₂.

In some embodiments, R^(A) is selected from those depicted in Table 1,below.

As defined above and described herein, R^(6′) is hydrogen or R^(A).

In some embodiments, R^(6′) is hydrogen. In some embodiments, R^(6′) isR^(A). In some embodiments, R^(6′) is ethyl. In some embodiments, R^(6′)is isopropyl. In some embodiments, R^(6′) is neopropyl. In someembodiments, R^(6′) is tert-butyl. In some embodiments, R^(6′) iscyclopropyl. In some embodiments, R^(6′) is cyclobutyl. In someembodiments, R^(6′) is cyclopentyl. In some embodiments, R^(6′) iscyclohexyl.

In some embodiments, R^(6′) is selected from those depicted in Table 1,below.

As defined above and described herein, R^(7′) is hydrogen, R^(A),halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)NROR, —OC(O)R, —OC(O)NR₂, —NRC(O)OR, —NRC(O)R,—NRC(O)NR₂, or —NRS(O)₂R.

In some embodiments, R^(7′) is hydrogen. In some embodiments, R^(7′) isR^(A). In some embodiments, R^(7′) is halogen. In some embodiments,R^(7′) is —CN. In some embodiments, R^(7′) is —NO₂. In some embodiments,R^(7′) is —OR. In some embodiments, R^(7′) is —SR. In some embodiments,R^(7′) is —NR₂. In some embodiments, R^(7′) is —S(O)₂R. In someembodiments, R^(7′) is —S(O)₂NR₂. In some embodiments, R^(7′) is —S(O)R.In some embodiments, R^(7′) is —C(O)R. In some embodiments, R^(7′) is—C(O)OR. In some embodiments, R^(7′) is —C(O)NR₂. In some embodiments,R^(7′) is —C(O)NROR. In some embodiments, R^(7′) is —OC(O)R. In someembodiments, R^(7′) is —OC(O)NR₂. In some embodiments, R^(7′) is—NRC(O)OR. In some embodiments, R^(7′) is —NRC(O)R. In some embodiments,R^(7′) is —NRC(O)NR₂. In some embodiments, R^(7′) is —NRS(O)₂R. In someembodiments, R^(7′) is

In some embodiments, R^(7′) is selected from those depicted in Table 1,below.

As defined above and described herein, p is 0, 1, 2, 3, or 4.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2. In some embodiments, p is 3. In some embodiments, pis 4.

In some embodiments, p is selected from those depicted in Table 1,below.

As defined above and described herein, L^(1′) is a covalent bond or abivalent, saturated or partially unsaturated, straight or branched C₁₋₅hydrocarbon chain, wherein 0-3 methylene units of L^(1′) areindependently replaced by —O—, —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—,or —S(O)₂-.

In some embodiments, L^(1′) is covalent bond. In some embodiments,L^(1′) is a bivalent, saturated or partially unsaturated, straight orbranched C₁₋₅ hydrocarbon chain, wherein 0-3 methylene units of L^(1′)are independently replaced by —O—, —NR—, —CRF—, —CF₂—, —C(O)—, —S—,—S(O)—, or —S(O)₂—. In some embodiments, L^(1′) is

In some embodiments, L^(1′) is

In some embodiments, L^(1′) is

In some embodiments, L^(1′) is

In some embodiments, L^(1′) is selected from those depicted in Table 1,below.

As defined above and described herein, L^(2′) is a covalent bond or abivalent, saturated or partially unsaturated, straight or branched C₁₋₅hydrocarbon chain, wherein 0-3 methylene units of L^(2′) areindependently replaced by —O—, —NR—, —CRF—, —CF₂—, —C(O)—, —S—, —S(O)—,or —S(O)₂-.

In some embodiments, L^(2′) is covalent bond. In some embodiments,L^(2′) is a bivalent, saturated or partially unsaturated, straight orbranched C₁₋₅ hydrocarbon chain, wherein 0-3 methylene units of L^(2′)are independently replaced by —O—, —NR—, —CRF—, —CF₂—, —C(O)—, —S—,—S(O)—, or —S(O)₂—. In some embodiments, L^(2′) is

In some embodiments, L^(2′) is selected from those depicted in Table 1,below.

As defined above and described herein, Q′ is a bivalent moiety selectedfrom —O—, —CR₂—, —CF₂—, —CFR—, —C(O)—, —OCR₂—, and —C(S)—.

In some embodiments, Q′ is —O—. In some embodiments, Q′ is —CR₂—. Insome embodiments, Q′ is —OCR₂—. In some embodiments, Q′ is —CF₂—. Insome embodiments, Q′ is —CFR—. In some embodiments, Q′ is —C(O)—. Insome embodiments, Q′ is —C(S)—.

In some embodiments, Q′ is selected from those depicted in Table 1,below.

As defined above and described herein, X¹ is an optionally substituted—(CH₂)_(x)—, wherein 1-2 methylenes of X¹ is optionally replaced with abivalent group selected from —NR—, —N(COR)—, —N(CO₂R)—, —N(SO₂R)—,—N(CONR₂)—, and —N(SO₂NR₂)—.

In some embodiments, X¹ is an optionally substituted —(CH₂)_(x)—. Insome embodiments, X¹ is an optionally substituted —(CH₂)_(x)—, wherein1-2 methylenes of X¹ is replaced with a bivalent group selected from—NR—, —N(COR)—, —N(CO₂R)—, —N(SO₂R)—, —N(CONR₂)—, and —N(SO₂NR₂)—. Insome embodiments, X′ is

In some embodiments, X′ is

As defined above and described herein, x is 0, 1, 2, 3, 4, or 5.

In some embodiments, x is 0. In some embodiments, x is 1. In someembodiments, x is 2. In some embodiments, x is 3. In some embodiments, xis 4. In some embodiments, x is 5.

In some embodiments, x is selected from those depicted in Table 1,below.

As defined above and described herein, Y′ is an optionally substituted—(CH₂)_(y)—.

In some embodiments, Y′ is an optionally substituted —(CH₂)_(y)—. Insome embodiments, Y′ is —CH₂—. In some embodiments, Y′ is

In some embodiments, Y′ is selected from those depicted in Table 1,below.

As defined above and described herein, y is 0, 1, 2, or 3.

In some embodiments, y is 0. In some embodiments, y is 1. In someembodiments, y is 2. In some embodiments, y is 3.

In some embodiments, y is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen or R^(A).

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is R^(A).In some embodiments, R_(3′) is

In some embodiments, R^(3′) is selected from those depicted in Table 1,below.

As defined above and described herein, R^(a1) and R^(a2) are eachindependently hydrogen, R^(A), —CH₂CO₂R, or —CH₂OCO₂R.

In some embodiments, R^(a1) is hydrogen. In some embodiments, R^(a1) isR^(A). In some embodiments, R^(a1) is —CH₂CO₂R. In some embodiments,R^(a1) is —CH₂OCO₂R. In some embodiments, R^(a2) is hydrogen. In someembodiments, R^(a2) is R^(A). In some embodiments, R^(a2) is —CH₂CO₂R.In some embodiments, R^(a2) is —CH₂OCO₂R.

As defined above and described herein, Ring M′ is an optionallysubstituted bivalent ring selected from phenylenyl, naphthylenyl, a 5-10membered heteroarylenyl containing 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a 5-11 membered saturated orpartially unsaturated carbocyclylenyl or heterocyclylenyl with 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;

In some embodiments, Ring M′ is an optionally substituted phenylenyl. Insome embodiments, Ring M′ is an optionally substituted naphthylenyl. Insome embodiments, Ring M′ is an optionally substituted 5-10 memberedheteroarylenyl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring M′ is anoptionally substituted 5-11 membered saturated or partially unsaturatedcarbocyclylenyl. In some embodiments, Ring M′ is an optionallysubstituted 5-11 membered saturated or partially unsaturatedheterocyclylenyl with 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring M′ is

In some embodiments, Ring M′ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring D′ is selected from phenyl,a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic,bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments, Ring D′ is phenyl. In some embodiments, Ring D′ is4-11 membered saturated or partially unsaturated monocyclic, bicyclic,bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, Ring D′ is 5-6 membered heteroaryl with 1-4heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring D′ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring W′ is an optionallysubstituted ring selected from a 5-9 membered saturated or partiallyunsaturated heterocyclyl.

In some embodiments, Ring W′ is an optionally substituted ring selectedfrom a 5-9 membered saturated or partially unsaturated heterocyclyl. Insome embodiments, Ring W′ is a 8- membered saturated heterocyclyl.

In some embodiments, Ring W′ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring U′ is a ring selected fromphenyl, a 5-6 membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, and a 5-7membered saturated or partially unsaturated carbocyclyl or heterocyclylwith 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In some embodiments, Ring U′ is phenyl. In some embodiments, Ring U′ isa 5-6 membered heteroaryl containing 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, Ring U′is a 5-7 membered saturated or partially unsaturated carbocyclyl orheterocyclyl with 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, Ring U′ is selected from those depicted in Table 1,below.

As defined above and described herein, R^(u′) is hydrogen, R^(A),halogen, —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—C(O)R, —C(O)OR, —C(O)NR₂, —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂,—OC(O)R, —OC(O)NR₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂,—NRC(O)OR, —NRC(O)R, —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂,—NRP(O)(OR)NR₂, —NRP(O)(NR₂)₂, or —NRS(O)₂R.

In some embodiments, R^(u′) is hydrogen. In some embodiments, R^(u′) isR^(A). In some embodiments, R^(u′) is halogen. In some embodiments,R^(u′) is —CN. In some embodiments, R^(u′) is —NO₂. In some embodiments,R^(u′) is —OR. In some embodiments, R^(u′) is —SR. In some embodiments,R^(u′) is —NR₂. In some embodiments, R^(u′) is —SiR₃. In someembodiments, R^(u′) is —S(O)₂R. In some embodiments, R^(u′) is—S(O)₂NR₂. In some embodiments, R^(u′) is —S(O)R. In some embodiments,R^(u′) is —C(O)R. In some embodiments, R^(u′) is —C(O)OR. In someembodiments, R^(u′) is —C(O)NR₂. In some embodiments, R^(u′) is—C(O)NROR. In some embodiments, R^(u′) is —CR₂NRC(O)R. In someembodiments, R^(u′) is —CR₂NRC(O)NR₂. In some embodiments, R^(u′) is—OC(O)R. In some embodiments, R^(u′) is —OC(O)NR₂. In some embodiments,R^(u′) is —OP(O)R₂. In some embodiments, R^(u′) is —OP(O)(OR)₂. In someembodiments, R^(u′) is —OP(O)(OR)NR₂. In some embodiments, R^(u′) is—OP(O)(NR₂)₂. In some embodiments, R^(u′) is —NRC(O)OR. In someembodiments, R^(u′) is —NRC(O)R. In some embodiments, R^(u′) is—NRC(O)NR₂. In some embodiments, R^(u′) is —NRS(O)₂R. In someembodiments, R^(u′) is —NP(O)R₂. In some embodiments, R^(u′) is—NRP(O)(OR)₂. In some embodiments, R^(u′) is —NRP(O)(OR)NR₂. In someembodiments, R^(u′) is —NRP(O)(NR₂)₂. In some embodiments, R^(u′) is—NRS(O)₂R. In some embodiments, R^(u′) is -iPr. In some embodiments,R^(u′) is —S(O)₂iPr. In some embodiments, R^(u′) is —S(O)₂CH₃.

As defined above and described herein, u is 0, 1, 2, 3, or 4.

In some embodiments, u is 0. In some embodiments, u is 1. In someembodiments, u is 2. In some embodiments, u is 3. In some embodiments, uis 4.

In some embodiments, u is selected from those depicted in Table 1,below.

As defined above and described herein, Ring V′ is an optionallysubstituted fused ring selected from a 6-membered aryl, a 5-6 memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partiallyunsaturated carbocyclyl or heterocyclyl with 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring V′ is an optionally substituted 6-memberedaryl. In some embodiments, Ring V′ is an optionally substituted 5-6membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, Ring V′ is anoptionally substituted 5-7 membered saturated or partially unsaturatedcarbocyclyl or heterocyclyl with 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, Ring V′ is a6-membered aryl.

In some embodiments, Ring V′ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring Z′ is a bivalent ringselected from phenylenyl, a 4-7 membered saturated or partiallyunsaturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and a 5-6membered heteroarylenyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In some embodiments, Ring Z′ is phenylenyl. In some embodiments, Ring Z′is a 4-7 membered saturated or partially unsaturated carbocyclylenyl. Insome embodiments, Ring Z′ is a heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring Z′ is a 5-6 membered heteroarylenyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Ring Z′ is

In some embodiments, Ring Z′ is

In some embodiments, Ring Z′ is

In some embodiments, Ring Z′ is selected from those depicted in Table 1,below.

As defined above and described herein, R^(z′) is hydrogen, R^(A),halogen, —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—C(O)R, —C(O)OR, —C(O)NR₂, —C(O)NROR, —CR₂NRC(O)R, —CR₂NRC(O)NR₂,—OC(O)R, —OC(O)NR₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂,—NRC(O)OR, —NRC(O)R, —NRC(O)NR₂, —NRS(O)₂R, —NP(O)R₂, —NRP(O)(OR)₂,—NRP(O)(OR)NR₂, —NRP(O)(NR₂)₂, or —NRS(O)₂R.

In some embodiments, R^(z′) is hydrogen. In some embodiments, R^(z′) isR^(A). In some embodiments, R^(z′) is halogen. In some embodiments,R^(z′) is —CN. In some embodiments, R^(z′) is —NO₂. In some embodiments,R^(z′) is —OR. In some embodiments, R^(z′) is —SR. In some embodiments,R^(z′) is —NR₂. In some embodiments, R^(z′) is —SiR₃. In someembodiments, R^(z′) is —S(O)₂R. In some embodiments, R^(z′) is—S(O)₂NR₂. In some embodiments, R^(z′) is —S(O)R, —C(O)R. In someembodiments, R^(z′) is —C(O)OR. In some embodiments, R^(z′) is —C(O)NR₂.In some embodiments, R^(z′) is —C(O)NROR. In some embodiments, R^(z′) is—CR₂NRC(O)R. In some embodiments, R^(z′) is —CR₂NRC(O)NR₂. In someembodiments, R^(z′) is —OC(O)R. In some embodiments, R^(z′) is—OC(O)NR₂. In some embodiments, R^(z′) is —OP(O)R₂. In some embodiments,R^(z′) is —OP(O)(OR)₂. In some embodiments, R^(z′) is —OP(O)(OR)NR₂. Insome embodiments, R^(z′) is —OP(O)(NR₂)₂. In some embodiments, R^(z′) is—NRC(O)OR. In some embodiments, R^(z′) is —NRC(O)R. In some embodiments,R^(z′) is —NRC(O)NR₂. In some embodiments, R^(z′) is —NRS(O)₂R. In someembodiments, R^(z′) is —NP(O)R₂. In some embodiments, R^(z′) is—NRP(O)(OR)₂. In some embodiments, R^(z′) is —NRP(O)(OR)NR₂. In someembodiments, R^(z′) is —NRP(O)(NR₂)₂. In some embodiments, R^(z′) is—NRS(O)₂R. In some embodiments, R^(z′) is —CH₃. In some embodiments,R^(z′) is —Cl. In some embodiments, R^(z′) is —F.

In some embodiments, R^(z′) is selected from those depicted in Table 1,below.

As defined above and described herein, z is 0, 1, 2, 3 or 4.

In some embodiments, z is 0. In some embodiments, z is 1. In someembodiments, z is 2. In some embodiments, z is 3. In some embodiments, zis 4.

In some embodiments, z is selected from those depicted in Table 1,below.

As defined above and described herein, n is 0 or 1.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, n is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-13:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, W, R^(a2), R^(z′), z, andn is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-14:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-15:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-16:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-17:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R², R^(z′), z, andn is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-18:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-19:

or a pharmaceutically acceptable salt thereof, wherein each of R^(2′),m, L, L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X¹, Y′, R^(a1), R^(a2),R^(z′), z, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments herein, structures depicted as

can include, for example structures

etc.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-20:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R_(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-21:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-22:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R_(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-23:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R_(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-24:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R_(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-25:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R_(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-26:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R_(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-27:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R_(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-28:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R², R^(z′), z, andn is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-20:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″, wherein DIM is

as shown, to provide a compound of formula II-r″-30:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), Ring M′, Ring Z′, R^(3′), Q′, X′, Y′, R^(a1), R^(a2), R^(z′), z,and n is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-31:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R′, Y′, Q′, R^(a1),R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-32:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-33:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-34:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R_(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-35:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-36:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-37:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-38:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-39:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-40:

or a pharmaceutically acceptable salt thereof, wherein each of X^(6′),R^(6′), L, L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′),Y′, Q′, R^(a1), R^(a2), R^(z′), z, and n is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-41:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-42:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-43:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-44:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-45:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R_(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-46:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-47:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-r″-7, wherein DIM is

as shown, to provide a compound of formula II-r″-48:

or a pharmaceutically acceptable salt thereof, wherein each of L,L^(1′), L^(2′), Ring M′, Ring U′, Ring W′, Ring Z′, R^(3′), Y′, Q′,R^(a1), R^(a2), R^(z′), z, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-5:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,Ring M′, Ring U′, Ring V′, R^(3′), Q, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-6:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,Ring M′, Ring U′, Ring V′, R^(3′), Q, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-7:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,Ring M′, Ring U′, Ring V′, R^(3′), Q, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-8:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-9:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-10:

or a pharmaceutically acceptable salt thereof, wherein each of R², m, L,Ring M′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-11:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-12:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-13:

or a pharmaceutically acceptable salt thereof, wherein each of X^(6′),R^(6′), L, Ring M′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), andR^(a2) is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-14:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-15:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-16:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-17:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-18:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-19:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-20:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula II-s″, wherein DIM is

as shown, to provide a compound of formula II-s″-21:

or a pharmaceutically acceptable salt thereof, wherein each of L, RingM′, Ring U′, Ring V′, R^(3′), Q′, X′, Y′, R^(a1), and R^(a2) is asdefined above and described in embodiments herein, both singly and incombination.

Without being limited to any particular theory, prodrugs of compounds offormula I and formula II are included in the present invention. It iswell established that a prodrug approach, wherein a compound isderivatized into a form suitable for formulation and/or administration,then released as a drug in vivo, has been successfully employed totransiently (e.g., bioreversibly) alter the physicochemical propertiesof the compound (see, H. Bundgaard, Ed., “Design of Prodrugs,” Elsevier,Amsterdam, (1985); R. B. Silverman, “The Organic Chemistry of DrugDesign and Drug Action,” Academic Press, San Diego, chapter 8, (1992);K. M. Hillgren et al., Med. Res. Rev., 15, 83 (1995)).

One of ordinary skill in the art will appreciate that the diflourophosphonate moiety described above may convert in vivo to a ketonephosphonate moiety, e.g.,

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aw or II-t:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², R³, R⁴, R⁵, R⁶, R₇, R⁸, R₉, R¹⁰, A, Z, X,Y, a, and b is as described and defined in WO 2010/121007 and US2012/0053208, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-ax or II-u:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ is asdescribed and defined in WO 2011/066263, WO 2012/097351, and U.S. Pat.No. 8,883,749, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-ay or II-v:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, Ar, X and Y is as described and defined in WO2011/081205 and US 2012/302524, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-az or II-w:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, and R₄ is as described and defined inWO 2011/163424 and US 2013/0172340, the entirety of each of which isherein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aaa or II-x:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, and R₄ is as described and defined inWO 2012/018868 and US 2013/0225621, the entirety of each of which isherein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aab or II-y:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₄, and X is as described and definedin WO 2012/078982, the entirety of each of which is herein incorporatedby reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aac or II-z:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₄, and R₅ is as described and definedin WO 2012/142615, the entirety of each of which is herein incorporatedby reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aad or II-aa:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₄, m, and n is as described anddefined in WO 2013/177534 and US 2015/0158894, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aae or II-bb:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₄, Y, and

is as described and defined in WO 2013/187965 and US 2015/0166484, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aaf or II-cc:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables Q¹, Q², Q³, and R¹ is as described and defined inWO 2014/028909 and US 2015/0232434, the entirety of each of which isherein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aag or II-dd:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², R³, R⁶, Z, and Y is as described anddefined in WO 2014/070859 and US 2015/0259366, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aah or II-ee:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R1, X1, X2, X3, X4, and X5 is as described anddefined in WO 2014/153495 and US 2016/0068478, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aai or II-ff:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, and R₃ is as described and defined in WO2014/205416 and US 2016/0137663, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aaj or II-hh:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variable R is as described and defined in US 2016/0060239,the entirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aak or II-ii:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables Ring A, Ring B, X₁, X₂, X₃, X₄, Y, Z, R_(A),R_(B), R_(C), R_(N), R_(X), L_(B), p, q, and

is as described and defined in WO 2016/089060 and US 2017/0320889, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aal or II-jj:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁ and R₂ is as described and defined in WO2016/115455, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aam or II-kk:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴ is as described and defined in WO 2016/125169 and US2018/0028475, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aan-1, I-aan-2, II-11-1, or II-11-2:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴ is as described and defined in WO 2016/193332 and US2018/0155360, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aao or II-mm:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R_(2′), R₃, R_(3′), R₄, R_(4′), R₅, R₆, A,X, Cy₁, and m is as described and defined in WO 2018/104295, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety therebyforming a compound of formula I-aap or II-nn:

or a pharmaceutically acceptable salt thereof, wherein L and LBM or DIMare as defined above and described in embodiments herein, and whereineach of the variables R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, Q, W, t, p, and yis as described and defined in WO 2018/136935, the entirety of each ofwhich is herein incorporated by reference.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in Dhanik, A. et al. Binding Modes ofPeptidomimetics Designed to Inhibit STAT3, PLoS ONE 2012, 7(12):e51603such as, for example:

or a pharmaceutically acceptable salt thereof, wherein

or is attached to a modifiable carbon, oxygen, or nitrogen atom.

In some embodiments, the present invention provides a compound formula Ior formula II, wherein STAT is a STAT3 binding moiety selected from acompound recited in Morlacchi, P. et al. Targeting SH2 domains in breastcancer, Future Med. Chem. 2014, 6(7): 1909 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in Qiu, H. Y. et al. Identification of NewShikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain,Sci. Rep. 2017, 7:2863 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein R is defined bycompounds PMM-158 to PMM-173 and

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in Yu. X. et al. Eriocalyxin B Inhibits STAT3Signaling by Covalently Targeting STAT3 and Blocking Phosporylation andActivation of STAT3, PLoS ONE 2015, 10(5):e0128406 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein or is attached toa modifiable carbon or oxygen atom.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in Kolosenko, I. et al. Identification of novelsmall molecule that inhibit STAT3-dependent transcription and function,PLoS ONE 2017, 12(6):e0178844 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in Zheng, W. et al. Discovery of monocarbonylcurcumin-BTP hydbrids as STAT3 inhibitors for drug-sensitive anddrug-resistant breast cancer therapy, Sci. Rep. 2017, 7:46352 such as,for example:

or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂ aredefined by compounds defined and described therein and

is attached to a modifiable carbon nitrogen, or oxygen atom.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in Zheng, W. et al. MMPP Attenuates Non-SmallCell Lung Cancer Growth by Inhibiting the STAT3 DNA-Binding Activity viaDirect Binding to the STAT3 DNA-Binding Domain, Theranostics 2017,7(18):4632 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon or oxygen atom.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT3 binding moiety selectedfrom a compound recited in Feng, T. et al. Arctigenin inhibits STAT3 andexhibits anticancer potential in human triple-negative breast cancertherapy, Oncotarget 2017, 8(1):329 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon or oxygen atom.

In some embodiments, the present invention provides a compound offormula I or formula II, wherein STAT is a STAT1 or STAT3 binding moietyselected from a compound recited in Szelag, M. et al. Identification ofSTAT1 and STAT3 Specific Inhibitors Using Comparitive Virtual Screeningand Docking Validation, PLoS ONE 2015, 10(2):e0116688 such as, forexample natural compounds (e.g., cryptotanshinone, curcumin,cucurbitacin E and cucurbitacin Q) or chemical substances of syntheticorigin (e.g., LLL12, FLLL32, Cpd188, Cpd30-12, STX-0119, HJC1023,S31-201, S31-201.1066, BP-1-102, OPB-31121, WP1066, RSVA314, andRSVA405), or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, the present invention provides a compound offormula II, wherein STAT is a STAT3 binding moiety selected from acompound recited in Chen, J. et al. Structure-Based Design ofConformationally Contstrained, Cell-Permeable STAT3Inhibitors, J. Med.Chem. Lett. 2010, 1:85 such as, for example:

or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon, oxygen, or nitrogen atom.

In some embodiments, the present invention provides a compound offormula II, wherein STAT is a STAT3 binding moiety selected from:

or a pharmaceutically acceptable salt thereof, wherein

is attached to a modifiable carbon oxygen, or nitrogen atom.

In certain embodiments, the present invention provides a compound offormula II, wherein STAT is a STAT3 binding moiety thereby forming acompound of formula II-yy-1 to II-yy-8:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are asdefined above and described in embodiments herein, and wherein each ofthe variables R, R¹, R², R³, R⁴, and R⁵ is as described and defined inJamroskovic, J. et al., Quinzoline Ligands Induce Cancer Call Deaththrough Selective STAT3Inhibition and G-Quadruplex Stabilization, J. Am.Chem. Soc., dx.doi.org/10.1021/jacs.9b11232, the entirety of each ofwhich is herein incorporated by reference.

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

In some embodiments, STAT is

As defined above and described herein, L is a bivalent moiety thatconnects STAT to LBM or STAT to DIM.

In some embodiments, L is a bivalent moiety that connects STAT to LBM.In some embodiments, L is a bivalent moiety that connects STAT to DIM.In some embodiments, L is a bivalent moiety that connects STAT to alysine mimetic.

In some embodiments, L is a covalent bond or a bivalent, saturated orpartially unsaturated, straight or branched C₁₋₅₀ hydrocarbon chain,wherein 0-6 methylene units of L are independently replaced by—C(D)(H)—, —C(D)₂-, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,—P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,—S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)C(O)O—,

wherein each -Cy- is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-11membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-11 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroarylenyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10.

In some embodiments, L is selected from those depicted in Table 1 orTable 1A, below.

In some embodiments, each -Cy- is independently an optionallysubstituted bivalent phenylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 8-10 membered bicyclic arylenyl.In some embodiments, each -Cy- is independently an optionallysubstituted 4-7 membered saturated or partially unsaturatedcarbocyclylenyl. In some embodiments, each -Cy- is independently anoptionally substituted 4-11 membered saturated or partially unsaturatedspiro carbocyclylenyl. In some embodiments, each -Cy- is independentlyan optionally substituted 8-10 membered bicyclic saturated or partiallyunsaturated carbocyclylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, each -Cy- is independently an optionally substituted 4-11membered saturated or partially unsaturated spiro heterocyclylenylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, each -Cy- isindependently an optionally substituted 5-6 membered heteroarylenylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments, -Cy- is selected from those depicted in Table 1 orTable 1A, below.

In some embodiments, r is 0. In some embodiments, r is 1. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, ris 4. In some embodiments, r is 5. In some embodiments, r is 6. In someembodiments, r is 7. In some embodiments, r is 8. In some embodiments, ris 9. In some embodiments, r is 10.

In some embodiments, r is selected from those depicted in Table 1 orTable 1A, below.

In some embodiments, L is a covalent bond. In some embodiments, L is

In some embodiments, L is

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In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is selected from those depicted in Table 1 orTable 1A, below.

Without limitation, the point of attachment of L to STAT and DIM can be,for example when L is

either

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is

selected from those wherein STAT is LBM is selected from any of those inTable A below, and L is selected from any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein STAT is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

TABLE A Exemplified E3 Ligase Binding Moiety (LBM)

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

(j)

(k)

(l)

(m)

(n)

(o)

(p)

(q)

(n)

(o)

(p)

(q)

(r)

(s)

(t)

(u)

(v)

(w)

(x)

(y)

(z)

(aa)

(bb)

(cc)

(dd)

(ee)

(ff)

(gg)

(hh)

(ii)

(jj)

(kk)

(ll)

(mm)

(nn)

(oo)

(pp)

(qq)

(rr)

(ss)

(tt)

(uu)

(vv)

(ww)

(xx)

(yy)

(zz)

TABLE B Exemplified Linkers (L)

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

(232)

(233)

(234)

(235)

(236)

(237)

(238)

(239)

(240)

(241)

(242)

(243)

(244)

(245)

(246)

(247)

(248)

(249)

(250)

(251)

(253)

(254)

(255)

(256)

(257)

(258)

(259)

(260)

(261)

(262)

(263)

(264)

(265)

(266)

(267)

(268)

(269)

(270)

(271)

(272)

(273)

(274)

(275)

(276)

(277)

(278)

(279)

(280)

(281)

(282)

(283)

(284)

(285)

(286)

(287)

(288)

(289)

(290)

(291)

(292)

(293)

(294)

(295)

(296)

(297)

(298)

(299)

(300)

(301)

(302)

(303)

(304)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(313)

(314)

(315)

(316)

(317)

(318)

(319)

(320)

(321)

(322)

(323)

(324)

(325)

(326)

(327)

(328)

(329)

(330)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(345)

(346)

(347)

(348)

(349)

(350)

(351)

(352)

(353)

(354)

(355)

(356)

(357)

(358)

(359)

(360)

(361)

(362)

(363)

(364)

(365)

(366)

(367)

(368)

(369)

(370)

(371)

(372)

(373)

(374)

(375)

(376)

(377)

(378)

(379)

(380)

(381)

(382)

(383)

(384)

(385)

(386)

(387)

(388)

(389)

(390)

(391)

(392)

(393)

(394)

(395)

(396)

(397)

(398)

(399)

(400)

(401)

(402)

(403)

(404)

(405)

(406)

(407)

(408)

(409)

(410)

(411)

(412)

(413)

(414)

(415)

(416)

(417)

(418)

(419)

(420)

(421)

(422)

(423)

(424)

(425)

(426)

(427)

(428)

(429)

(430)

(431)

(432)

(433)

(434)

(435)

(436)

(437)

(438)

(438)

(439)

(440)

(441)

(442)

(443)

(444)

(445)

(446)

(447)

(448)

(449)

(450)

(451)

(452)

(453)

(454)

(455)

(456)

(457)

(458)

(459)

(460)

(461)

(462)

(463)

(464)

(465)

(466)

(467)

(468)

(469)

(470)

(471)

(472)

(473)

(474)

(475)

(475)

(476)

(477)

(478)

(479)

(480)

(481)

(482)

(483)

(484)

(485)

(486)

(487)

(488)

(489)

(490)

(491)

(492)

(493)

(494)

(495)

(496)

(497)

(498)

(499)

(500)

(501)

(502)

(503)

(504)

(505)

(506)

(507)

(508)

(509)

(510)

(511)

(512)

(513)

(514)

(515)

(516)

(517)

(518)

(519)

(520)

(521)

(522)

(523)

(524)

(525)

(526)

(527)

(528)

(529)

(530)

(531)

(532)

(533)

(534)

(535)

(536)

(537)

(538)

(539)

(540)

(541)

(542)

(543)

(544)

(545)

(546)

(547)

(548)

(549)

(550)

(551)

(552)

(553)

(554)

(555)

(556)

(557)

(558)

(559)

(560)

(561)

(562)

(563)

(564)

(565)

(566)

(567)

(568)

(569)

(570)

(571)

(572)

(573)

(574)

(575)

(576)

(577)

(578)

(579)

(580)

(581)

(582)

(583)

(584)

(585)

(586)

(587)

(588)

(589)

(590)

(591)

(592)

(593)

(594)

(595)

(596)

(597)

(598)

(599)

(600)

(601)

(602)

(603)

(604)

(605)

(606)

(607)

(608)

(609)

(610)

(611)

(612)

(613)

(614)

(615)

(616)

(617)

(618)

(619)

(620)

(621)

(622)

(623)

(624)

(625)

(626)

(627)

(628)

(629)

(630)

(631)

(632)

(633)

(634)

(635)

(636)

(637)

(638)

(639)

(640)

(641)

(642)

(643)

(644)

(645)

(646)

(647)

(648)

(649)

(650)

(651)

(652)

(653)

(654)

(655)

(656)

(657)

(658)

(659)

(660)

(661)

(662)

(663)

(664)

(665)

(666)

(667)

(668)

(669)

(670)

(671)

(672)

(673)

(674)

(675)

(676)

(677)

(678)

(679)

(680)

(681) covalent bond, (682)

(683)

(684)

(685)

(686)

(687)

In some embodiments, the present invention provides a compound having aSTAT3 binding moiety described and disclosed herein, a LBM set forth inTable A above, and a linker set forth in Table B above, or apharmaceutically acceptable salt thereof.

Exemplary compounds of the invention are set forth in Table 1 and Table1A, below.

TABLE 1 Exemplary Compounds I-# Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof. Insome embodiments, the present invention provides a compound set forth inTable 1 as a diammonium salt.

Further exemplary compounds of the invention are set forth in Table 1A,below.

TABLE 1A Exemplary Compounds I-# Structure I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

In some embodiments, the present invention provides a compound set forthin Table 1A, above, or a pharmaceutically acceptable salt thereof.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group, leavinggroup, or transformation condition is depicted, one of ordinary skill inthe art will appreciate that other protecting groups, leaving groups,and transformation conditions are also suitable and are contemplated.Such groups and transformations are described in detail in March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B.Smith and J. March, 5^(th) Edition, John Wiley & Sons, 2001,Comprehensive Organic Transformations, R. C. Larock, 2^(nd) Edition,John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,the entirety of each of which is hereby incorporated herein byreference.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Examplesof suitable hydroxyl protecting groups include, but are not limited to,esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkylethers, and alkoxyalkyl ethers. Examples of such esters includeformates, acetates, carbonates, and sulfonates. Specific examplesinclude formate, benzoyl formate, chloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate,pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate,p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Suitableamino protecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

In the schemes below, where a final degrader is formed having a freeamine DIM moiety, it is not shown but it is generally appreciated andwell known by those having ordinary skill in the art that the reactivityof said free amine may be masked by employing a suitable aminoprotecting group that can thereafter be removed in situ or during aseparate synthetic step to form the final degrader product.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 1 set forth below:

As depicted in Scheme 1, above, amine A-1 is coupled to acid A-2 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between STAT and the terminalamino group of A-1 or the portion of the linker between DIM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 2 set forth below:

As depicted in Scheme 2, above, amine A-1 is coupled to acid A-2 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond,

represents the portion of the linker between STAT and the terminal aminogroup of A-1 or the portion of the linker between DIM and the terminalcarboxyl group of A-2, respectively. Additionally, an amide bond can beformed using coupling reagents known in the art such as, but not limitedto DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P,TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 3 set forth below:

As depicted in Scheme 3, above, acid A-3 is coupled to amine A-4 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between STAT and the terminalcarboxyl group of A-3 or the portion of the linker between DIM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 4 set forth below:

As depicted in Scheme 4, above, acid A-3 is coupled to amine A-4 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond,

, represents the portion of the linker between STAT and the terminalcarboxyl group of A-3 or the portion of the linker between DIM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 5 set forth below:

As depicted in Scheme 5, above, an S_(N)Ar displacement of fluoride A-6by amine A-5 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between STAT and the terminalamino group of A-5.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 6 set forth below:

As depicted in Scheme 6, above, an S_(N)Ar displacement of fluoride A-7by amine A-8 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between DIM and the terminalamino group of A-8.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 7 set forth below:

As depicted in Scheme 7, above, reductive alkylation of aldehyde A-9 byamine A-10 is effected in the presence of a mild hydride source (e.g.,sodium cyanoborohydride or sodium triacetoxyborohydride) to form aprovided compound with a linker comprising a secondary amine. Thesquiggly bond,

, represents the portion of the linker between DIM and the terminalamino group of A-10.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 8 set forth below:

As depicted in Scheme 8, above, reductive alkylation of aldehyde A-12 byamine A-11 is effected in the presence of a mild hydride source (e.g.,sodium cyanoborohydride or sodium triacetoxyborohydride) to form aprovided compound with a linker comprising a secondary amine. Thesquiggly bond,

, represents the portion of the linker between STAT and the terminalamino group of A-11.

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. See for example, “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entirety of each of which isherein incorporated by reference. Such interconversions may require oneor more of the aforementioned techniques, and certain methods forsynthesizing compounds of the invention are described below in theExemplification.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably degrade and/or inhibit a STATprotein, or a mutant thereof, in a biological sample or in a patient. Incertain embodiments, the amount of compound in compositions of thisinvention is such that is effective to measurably degrade and/or inhibitan STAT protein, or a mutant thereof, in a biological sample or in apatient. In certain embodiments, a composition of this invention isformulated for administration to a patient in need of such composition.In some embodiments, a composition of this invention is formulated fororal administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily or degratorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof a STAT protein, or a mutant thereof.

As used herein, the term “degratorily active metabolite or residuethereof” means that a metabolite or residue thereof is also a degraderof an STAT protein, or a mutant thereof.

In certain embodiments, a provided compound is administered as aprodrug.

The term “prodrug” refers to a compound that is made more active invivo. A provided compound can also exist as prodrugs, as described inHydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, andEnzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich,Switzerland 2003). Prodrugs of the provided compounds described hereinare structurally modified forms of the compound that readily undergochemical changes under physiological conditions to provide the compound.Additionally, prodrugs can be converted to the compound by chemical orbiochemical methods in an ex vivo environment. For example, prodrugs canbe slowly converted to a compound when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the compound, or parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. A wide variety of prodrug derivatives are known inthe art, such as those that rely on hydrolytic cleavage or oxidativeactivation of the prodrug. An example, without limitation, of a prodrugwould be a compound which is administered as a phosphonate ester (the“prodrug”), but then is metabolically hydrolyzed to the phosphonic acidor a conjugate base thereof, the active entity. Additional examplesinclude peptidyl derivatives of a compound. The term “therapeuticallyacceptable prodrug,” refers to those prodrugs or zwitterions which aresuitable for use in contact with the tissues of patients without unduetoxicity, irritation, and allergic response, are commensurate with areasonable benefit/risk ratio, and are effective for their intended use.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for thedegradation and/or inhibition of STAT protein activity.

Examples of STAT protein that are degraded and/or inhibited by thecompounds and compositions described herein and against which themethods described herein are useful include those of the signaltransducer and activators of transcription (STAT) family of proteins,the members of which include STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6, or a mutant thereof. Yu et al., “Crosstalk between cancer andimmune cells: Role of STAT3 in the tumour microenvironment” Nat. Rev.Immunol. 2007, 7, 41-51, Levy et al., “STATs: Transcriptional controland biological impact” Nat. Rev. Mol. Cell Biol. 2002, 3, 651-662, theentirety of each of which is herein incorporated by reference.

The activity of a compound utilized in this invention as a degraderand/or inhibitor of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6, or a mutant thereof, may be assayed in vitro, in vivo or in acell line. In vitro assays include assays that determine inhibition ofeither the activity and/or the subsequent functional consequences ofactivated STAT protein, or a mutant thereof. Alternate in vitro assaysquantitate the ability of the inhibitor to bind to a STAT protein.Inhibitor binding may be measured by radiolabeling the inhibitor priorto binding, isolating the inhibitor/STAT complex and determining theamount of radiolabel bound. Alternatively, inhibitor binding may bedetermined by running a competition experiment where new inhibitors areincubated with a STAT protein bound to known radioligands.Representative in vitro and in vivo assays useful in assaying a STATinhibitor include those described and disclosed in, e.g., Schust et al.,“A high-throughput fluorescence polarization assay for signal transducerand activator of transcription 3” Anal. Biochem. 2004, 333(1):114;Muller et al., “A high-throughput assay for signal transducer andactivator of transcription 5b based on fluorescence polarization” Anal.Biochem. 2008, 375(2):249. Detailed conditions for assaying a compoundutilized in this invention as a degrader and/or inhibitor of STATproteins, or a mutant thereof, are set forth in the Examples below.

The STAT family of proteins are cytoplasmic transcription factors withimportant roles in mediating responses to cytokines and growth factors,including promoting cell growth and differentiation, and inflammationand immune responses (Bromberg et al., Breast Cancer Res. 2000, 2:86-90;Darnell et al., Nat. Rev. Cancer 2002, 2:740-749). STAT proteins areclassically activated by tyrosine (Tyr) kinases, such as Janus kinases(JAKs) and Src family kinases, in response to the binding of cytokineand growth factors to their cognate receptors (Darnell et al., Science1994, 264:1415). The Tyr phosphorylation (pTyr) promotes dimerizationbetween two activated STAT:STAT monomers through a reciprocal pTyr-Srchomology SH2 domain interactions. Active STAT:STAT dimers translocate tothe nucleus to induce gene transcription by binding to specificDNA-response elements in the promoters of target genes to regulate geneexpression. By contrast, aberrantly-active STAT3, one of the STAT familymembers, has been implicated in many human tumors and represents anattractive target for drug discovery. Persistently activated STAT3 and,to some extent, STAT5 increase tumour cell proliferation, survival andinvasion while suppressing anti-tumour immunity. The persistentactivation of STAT3 also mediates tumour-promoting inflammation. Thisaberrant activation of STAT3 occurs in glioma, breast, prostate,ovarian, and many other human cancers, whereby it promotes malignantprogression (Yu & Jove, Nat. Rev. Cancer 2004, 4:97-105). JAKs, Src, andepidermal growth factor receptor (EGFR) are STAT3 upstream regulators(Bromberg et al., Mol. Cell. Biol. 1998, 18:2553; Sartor et al., CancerRes. 1997, 57:978; Garcia et al., Oncogene 2001, 20:2499). Mechanisms bywhich constitutively-active STAT3 mediates tumorigenesis includedysregulation of gene expression that leads to uncontrolled growth andsurvival of tumor cells, enhanced tumor angiogenesis, and metastasis andthe suppression of tumor immune surveillance (Yu & Jove 2004; Bromberg &Darnell, Oncogene 2000, 19:2468-2473; Bowman et al., Oncogene 2000,19:2474-2488; Turkson & Jove, Oncogene 2000, 19:6613-6626; Turkson,Expert Opin. Ther. Targets 2004, 8:409-422; Wang et al., Nat. Med. 2004,10:48-54).

The main domains of STAT3 protein include the tetramerization andleucine zipper at the N-terminus, the DNA binding domain, and the SH2transactivation domain at the carboxy-terminal end. The SH2 region isresponsible for the binding of STAT3 to the tyrosine-phosphorylatedreceptors and for the dimerization which is necessary for DNA bindingand gene expression (Zhong et al., Science 1994, 264:95). STAT3 isactivated by phosphorylation at Y-705, which leads to dimer formation,nuclear translocation, recognition of STAT3-specific DNA bindingelements, and activation of target gene transcription (Damell 1994;Zhong 1994).

The constitutive activation of STAT3 is frequently detected in breastcarcinoma cell lines but not in normal breast epithelial cells (Garciaet al., Cell. Growth. Differ. 1997, 8:1267; Bowman 2000). It has beenreported that approximately 60 percent of breast tumors containpersistently activated STAT3 (Dechow et al., Proc. Natl. Acad. Sci. USA2004, 101:10602). STAT3 has been classified as a proto-oncogene becauseactivated STAT3 can mediate oncogenic transformation in cultured cellsand tumor formation in nude mice (Bromberg et al., Cell 1999, 98:295).STAT3 may participate in oncogenesis by stimulating cell proliferation,promoting angiogenesis, and conferring resistance to apoptosis inducedby conventional therapies (Catlett-Falcone et al., Curr. Opin. Oncol.1999, 11:1; Catlett-Falcone et al., Immunity 1999, 10:105; Alas et al.,Clin. Cancer Res. 2003, 9:316; Wei et al., Oncogene 2003, 22:1517).Possible downstream targets through which STAT3 promotes oncogenesisinclude up-regulation of anti-apoptotic factors (Bcl-2, survivin, Mcl-1,and Bcl-X_(L)), cell-cycle regulators (cyclin D1, MEK5, and c-myc), andinducer of tumor angiogenesis (VEGF) (Bromberg et al., Cell 1999,98:295; Wei et al., Oncogene 2003, 22:1517; Real et al., Oncogene 2002,21:7611; Puthier et al., Eur. J. Immunol. 1999, 29:3945; Niu et al.,Oncogene 2002, 21:2000; Kiuchi et al., J. Exp. Med. 1999, 189:63; Songet al., Oncogene 2004, 23:8301). Activated STAT3 signaling directlycontributes to malignant progression of cancer. STAT3 oncogenic functionacts through the pro-survival proteins such as survivin, Mcl-1, Bcl-2,and Bcl-X_(L) and results in the prevention of apoptosis (Real et al.,Oncogene 2002, 21:7611; Aoki et al., Blood 2003, 101:1535;Epling-Burnette et al., J. Clin. Invest. 2001, 107:351; Nielsen et al.,Leukemia 1999, 13:735). Blockade of STAT3 signaling inhibits cancer cellgrowth, demonstrating that STAT3 is essential to the survival or growthof tumor cells (Alas et al., Clin. Cancer Res. 2003, 9:316; Aoki et al.,Blood 2003, 101:1535; Epling-Bumette et al., J. Clin. Invest. 2001,107:351; Burke et al., Oncogene 2001, 20:7925; Mora et al., Cancer Res.2002, 62:6659; Ni et al., Cancer Res. 2000, 60:1225; Rahaman et al.,Oncogene 2002, 21:8404).

Recent evidence also reveals the role of STAT3 in modulatingmitochondrial functions and STAT3 crosstalk with other proteins, such asNF-κB, that promotes the malignant phenotype. Many human tumors harboraberrantly-active STAT3 signaling, and studies in experimental modelsindicate tumor cells and tumors harboring constitutively-active STAT3are responsive to STAT3 signaling modulators (Gough et al., Science2009, 324:1713; Yu et al., Nat. Rev. Cancer 2009, 9:798; Grivennikov &Karin, Cytokine & Growth Factor Rev. 2010, 21:11).

Representative STAT inhibitors include those described and disclosed ine.g., Morlacchi et al. Future Med. Chem. 2014, 6(7):1909; Sgrignani etal. Int. J. Mol. Sci. 2018, 19:1591, Botta et al. Mol. Inf. 2015,34:689; Leung et al. Methods 2015, 71:38; Lavecchia et al. Cur. Med.Chem. 2011, 18:1; Chun et al. Can. Lett. 2015, 357:393; Zhang et al.Eur. J. Med. Chem. 2017, 125:538; Yesylevskyy et al. J. Chem. Inf.Model. 2016, 56:1588; Huang et al. Bioorg. Med. Chem. Lett. 2016,26:5172; Gao et al. Bioorg. Med. Chem. 2016, 24:2549; Daka et al.Bioorg. Med. Chem. 2015, 23:1348; Ji et al. Bioorg. Med. Chem. 2016,24:6174; Zhou et al. Bioorg. Med. Chem. 2017, 25:2995; and Yu et al. J.Med. Chem. 2017, 60:2718; Chen et al. Med. Chem. Lett. 2010, 1:85; theentirety of each of which is herein incorporated by reference.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are degraders and/or inhibitors of one of more STATprotein and are therefore useful for treating one or more disordersassociated with activity of one or more of STAT protein. Thus, incertain embodiments, the present invention provides a method fortreating a STAT1-mediated, STAT2-mediated, STAT3-mediated,STAT4-mediated, STAT5A-mediated, STAT5B-mediated, or STAT6-mediateddisorder comprising the step of administering to a patient in needthereof a compound of the present invention, or pharmaceuticallyacceptable composition thereof.

As used herein, the terms “STAT1-mediated”, “STAT2-mediated”,“STAT3-mediated”, “STAT4-mediated”, “STAT5A-mediated”,“STAT5B-mediated”, and/or “STAT6-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which one or more STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6, or a mutant thereof, are known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in which oneor more STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6, or amutant thereof, are known to play a role.

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition is a cancer, a neurodegenative disorder,a viral disease, an autoimmune disease, an inflammatory disorder, ahereditary disorder, a hormone-related disease, a metabolic disorder,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, a cardiovascular disorder, or aCNS disorder.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer (see, e.g., Turkson &Jove, Oncogene 2000, 19:6613-6626), diabetes (see, e.g., Gurzov et al.,FEBS 2016, 283:3002), cardiovascular disease (see, e.g., Grote et al.,Vasc. Pharmacol. 2005, 43:2005), viral disease (see, e.g., Gao et al.,J. Hepatol. 2012, 57(2):430), autoimmune diseases such as lupus (see,e.g., Goropevsek et al., Clin. Rev. Alleg. & Immun. 2017, 52(2):164),and rheumatoid arthritis see, e.g., Walker & Smith, J. Rheumat. 2005,32(9):1650), autoinflammatory syndromes (see, e.g., Rauch et al.,Jak-Stat 2013, 2(1):e23820), atherosclerosis (see, e.g., Ortiz-Munoz etal., Arterio., Thrombo., Vasc. Bio. 2009, 29:525), psoriasis (see, e.g.,Andrés et al., Exp. Derm. 2013, 22(5):323), allergic disorders (see,e.g., Oh et al., Eur. Respir. Rev. 2019, 19(115):46), inflammatory boweldisease (see, e.g., Sugimoto, World J. Gastroenterol. 2008,14(33):5110), inflammation (see, e.g., Tamiya et al., Arterio.,Thrombo., Vasc. Bio. 2011, 31:980), acute and chronic gout and goutyarthritis, neurological disorders (see, e.g., Campbell, Brain Res. Rev.2005, 48(2):166), metabolic syndrome, immunodeficiency disorders such asAIDS and HIV (see, e.g., O'Shea et al., N. Engl. J. Med. 2013, 368:161),destructive bone disorders (see, e.g., Jatiani et al., Genes & Can.2011, 1(10):979), osteoarthritis, proliferative disorders, Waldenström'sMacroglobulinemia (see, e.g., Hodge et al., Blood 2014, 123(7):1055)infectious diseases, conditions associated with cell death, pathologicimmune conditions involving T cell activation, and CNS disorders in apatient. In one embodiment, a human patient is treated with a compoundof the current invention and a pharmaceutically acceptable carrier,adjuvant, or vehicle, wherein said compound is present in an amount tomeasurably degrade and/or inhibit one or more STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6, or a mutant thereof

Compounds of the current invention are useful in the treatment of aproliferative disease selected from a benign or malignant tumor, solidtumor, liquid tumor, carcinoma of the brain, kidney, liver, adrenalgland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum,prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract,esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas,neuroblastomas, multiple myeloma, gastrointestinal cancer, especiallycolon carcinoma or colorectal adenoma, a tumor of the neck and head, anepidermal hyperproliferation, psoriasis, prostate hyperplasia, aneoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, anMyD88 driven disorder, Smoldering of indolent multiple myeloma, orhematological malignancies (including leukemia, diffuse large B-celllymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,intravascular large B-cell lymphoma).

In some embodiments, the aberrant activation of STAT3 which can betreated according to the methods of this invention is a human cancer. Insome embodiments, the human cancer which can be treated according to themethods of this invention is selected from glioma, breast cancer,prostate cancer, head and neck squamous cell carcinoma, skin melanomas,and ovarian cancer. In some embodiments, abnormal STAT3 activation alsocorrelates with the progression of diverse hematopoietic malignancies,such as various leukemias and lymphomas, and STAT3 is frequentlyactivated in both multiple myeloma cell lines and tumor cell linesderived from patient bone marrows.

In some embodiments, the present invention provides a method of treatinga cancer selected from glioma, breast cancer, prostate cancer, head andneck squamous cell carcinoma, skin melanomas, ovarian cancer, malignantperipheral nerve shealth tumors (MPNST), pancreatic cancer, non-smallcell lung cancer, urothelial cancer, liver cancer, bile duct cancer,kidney cancer, colon cancer, esophageal cancer, gastric cancer,gastrointestinal stromal tumors, and hematological malignancies includelymphomas, leukemias, myelomas, myeloproliferative neoplasms andmyelodysplastic syndromes.

In some embodiments, the present invention provides a method of treatinga JAK-associated disease. In some embodiments, the JAK-associateddisease is cancer including those characterized by solid tumors (e.g.,prostate cancer, renal cancer, hepatic cancer, pancreatic cancer,gastric cancer, breast cancer, lung cancer, cancers of the head andneck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman'sdisease, uterine leiomyosarcoma, melanoma etc.), hematological cancers(e.g., lymphoma, leukemia Such as acute lymphoblastic leukemia (ALL),acute myelogenous leukemia (AML) or multiple myeloma), and skin cancersuch as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.Example CTCLs include Sezary syndrome and mycosis fungoides.

In some embodiments, the present invention provides a method of treatingtriple negative breast cancer in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present invention provides a method of treatingmalignant peripheral nerve sheath tumors (MPNST) in a patient in needthereof, comprising administering a compound of the present invention,or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method of treatinglung cancer, in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present invention provides a method of treatingcolorectal cancer, in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present invention provides a method of treatingperipheral T-cell lymphoma, in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present invention provides a method of treatingpancreatic cancer in a patient in need thereof, comprising administeringa compound of the present invention, or a pharmaceutically acceptablesalt thereof.

Compounds according to the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.

Compounds according to the invention are useful in the treatment ofheteroimmune diseases. Examples of such heteroimmune diseases include,but are not limited to, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis.

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, such as therapy for orintended to restrict or abort symptomatic attack when it occurs, forexample antiinflammatory or bronchodilatory. Prophylactic benefit inasthma may in particular be apparent in subjects prone to “morningdipping”. “Morning dipping” is a recognized asthmatic syndrome, commonto a substantial percentage of asthmatics and characterized by asthmaattack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Compounds of the current invention can be used for other inflammatory orobstructive airways diseases and conditions to which the presentinvention is applicable and include acute lung injury (ALI), adult/acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonary,airways or lung disease (COPD, COAD or COLD), including chronicbronchitis or dyspnea associated therewith, emphysema, as well asexacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, but not limited to, acute, arachidic, catarrhal, croupus,chronic or phthinoid bronchitis. Further inflammatory or obstructiveairways diseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

With regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, compounds of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil-related disorders ofthe airways consequential or concomitant to Loffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophilia), bronchopulmonary aspergillosis,polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma and eosinophil-related disorders affecting the airwaysoccasioned by drug-reaction.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, systemic lupus erythematosus, pemphigus vulgaris,pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosaacquisita, acne vulgaris, and other inflammatory or allergic conditionsof the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hyperchlolesterolemia, heart disease, chronic heartfailure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments, the present invention provides a method of treatingan autoimmune disease selected from systemic sclerosis, idiopathicpulmonary fibrosis, inflammatory bowel disease, atopic dermatitis,rheumatoid arthritis, graft versus host disease (acute and chronic), andother tissue fibrosis diseases.

In some embodiments, the present invention provides a method of treatinga hematologic malignancy selected from LGL leukemia (T and NK cell),cutaneous T cell lymphoma (CTCL), peripheral T cell lymphomas (PTCL, allsubtypes including ALCL), diffuse large B cell lymphoma (DLBCL), acutemyelogenous leukemia, multiple myeloma, and myelofibrosis

In some embodiments, the present invention provides a method of treatingtissue fibrosis or chronic tissue disease, including liver and kidneyfibrosis, in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present invention provides a method of treatingidiopathic interstitial pneumonia(s) (IIPs), including any type of lungfibrosis, either interstitial lung disease associated with rheumatoiddisease (including SSc) or IPF itself, in a patient in need thereof,comprising administering a compound of the present invention, or apharmaceutically acceptable salt thereof.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is an disease of the skin. Insome embodiments, the inflammatory disease of the skin is selected fromcontact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigusvulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysisbullosa acquisita, and other inflammatory or allergic conditions of theskin.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenileidiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome(CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a TH17 mediated disease.In some embodiments the TH17 mediated disease is selected from Systemiclupus erythematosus, Multiple sclerosis, and inflammatory bowel disease(including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis.

Cardiovascular diseases which can be treated according to the methods ofthis invention include, but are not limited to, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke,congestive heart failure, angina pectoris, reocclusion afterangioplasty, restenosis after angioplasty, reocclusion afteraortocoronary bypass, restenosis after aortocoronary bypass, stroke,transitory ischemia, a peripheral arterial occlusive disorder, pulmonaryembolism, and deep venous thrombosis.

In some embodiments, the neurodegenerative disease which can be treatedaccording to the methods of this invention include, but are not limitedto, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease, cerebral ischemia, andneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolicsyndrome, obesity, organ transplantation and graft versus host disease.

In some embodiments the invention provides a method of treating,preventing or lessening the severity of Alzheimer's disease comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt or composition thereof.

In some embodiments the invention provides a method of treating adisease or condition commonly occurring in connection withtransplantation. In some embodiments, the disease or condition commonlyoccurring in connection with transplantation is selected from organtransplantation, organ transplant rejection, and graft versus hostdisease.

In some embodiments the invention provides a method of treating ametabolic disease. In some embodiments the metabolic disease is selectedfrom Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.

In some embodiments the invention provides a method of treating a viraldisease. In some embodiments, the viral infection is HIV infection.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of a proliferative disease, an inflammatory disease, anobstructive respiratory disease, a cardiovascular disease, a metabolicdisease, a neurological disease, a neurodegenerative disease, a viraldisease, or a disorder commonly occurring in connection withtransplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

One or more other therapeutic agent may be administered separately froma compound or composition of the invention, as part of a multiple dosageregimen. Alternatively, one or more other therapeutic agents may be partof a single dosage form, mixed together with a compound of thisinvention in a single composition. If administered as a multiple dosageregime, one or more other therapeutic agent and a compound orcomposition of the invention may be administered simultaneously,sequentially or within a period of time from one another, for examplewithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments,one or more other therapeutic agent and a compound or composition of theinvention are administered as a multiple dosage regimen within greaterthan 24 hours apart.

In one embodiment, the present invention provides a compositioncomprising a provided compound and one or more additional therapeuticagents. The therapeutic agent may be administered together with aprovided compound, or may be administered prior to or followingadministration of a provided compound. Suitable therapeutic agents aredescribed in further detail below. In certain embodiments, a providedcompound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. Inother embodiments, a provided compound may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursfollowing the therapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating gout comprising administering to a patient in need thereof aprovided compound and one or more additional therapeutic agents selectedfrom non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine(Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol and febuxostat (Uloric®).

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a provided compound and one or more additional therapeuticagents selected from non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarialssuch as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®),methotrexate (Rheumatrex®), gold salts such as gold thioglucose(Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®),D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®),cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine(Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such asetanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®),certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-I”agents such as anakinra (Kineret®) and rilonacept (Arcalyst®),antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such asabatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab(Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof aprovided compound and one or more additional therapeutic agents selectedfrom acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) andmonoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatinglupus comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromacetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®),methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatinginflammatory bowel disease comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot® and anticholinergics or antispasmodics such as dicyclomine(Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagylor ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In some embodiments, the present invention provides a method of treatingHIV comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromnucleoside reverse transcriptase inhibitors such as zidovudine(Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®),abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®),emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine(Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®),non-nucleoside reverse transcriptase inhibitors such as delavirdine(Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) andetravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and one or more additionaltherapeutic agents selected from rituximab (Rituxan®), cyclophosphamide(Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinationsthereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating Waldenström's macroglobulinemia comprising administering to apatient in need thereof a provided compound and one or more additionaltherapeutic agents selected from chlorambucil (Leukeran®),cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine(Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, and a SYK inhibitor.

In some embodiments, one or more other therapeutic agent is anantagonist of the hedgehog pathway. Approved hedgehog pathway inhibitorswhich may be used in the present invention include sonidegib (Odomzo®,Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib(Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

In some embodiments, one or more other therapeutic agent is a histonedeacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor isselected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®,Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®,Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals)(NCT00866333); and chidamide (Epidaza®, HBI-8000, ChipscreenBiosciences, China).

In some embodiments, one or more other therapeutic agent is a CDKinhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib(Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); andtrilaciclib (G1T28, G1 Therapeutics).

In some embodiments, one or more other therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is a CCchemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studiedthat may be useful in the present invention include mogamulizumab(Poteligeo®, Kyowa Hakko Kirin, Japan).

In some embodiments, one or more other therapeutic agent is anisocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studiedwhich may be used in the present invention include AG120 (Celgene;NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032(Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, one or more other therapeutic agent is aglutaminase inhibitor. Glutaminase inhibitors being studied which may beused in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, one or more other therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (Rituxan®,Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®,GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech),ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, SpectrumPharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics);trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); andpertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, one or more other therapeutic agent is atopoisomerase inhibitor. Approved topoisomerase inhibitors useful in thepresent invention include irinotecan (Onivyde®, MerrimackPharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomeraseinhibitors being studied which may be used in the present inventioninclude pixantrone (Pixuvri®, CTI Biopharma).

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (Xtandi®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (Zytiga®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is an inhibitorof bone resorption. An approved therapeutic which inhibits boneresorption is Denosumab (Xgeva®, Amgen), an antibody that binds toRANKL, prevents binding to its receptor RANK, found on the surface ofosteoclasts, their precursors, and osteoclast-like giant cells, whichmediates bone pathology in solid tumors with osseous metastases. Otherapproved therapeutics that inhibit bone resorption includebisphosphonates, such as zoledronic acid (Zometa®, Novartis).

In some embodiments, one or more other therapeutic agent is an inhibitorof interaction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agent is an inhibitorof transforming growth factor-beta (TGF-beta or TGFB). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences8:964-978. One therapeutic compound currently in clinical trials fortreatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X),which is a bispecific, anti-PD-L1/TGFB trap compound (NCT02699515); and(NCT02517398). M7824 is comprised of a fully human IgG1 antibody againstPD-L1 fused to the extracellular domain of human TGF-beta receptor II,which functions as a TGFB “trap.”

In some embodiments, one or more other therapeutic agent is selectedfrom glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), ananti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxicMMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells' ability to metastasize.

In some embodiments, one or more other therapeutic agent is anantiproliferative compound. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; matrix metalloproteinase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (Temodal®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

In some embodiments, the present invention provides a method of treatingAlzheimer's disease comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from donepezil (Aricept®), rivastigmine (Excelon®),galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

In some embodiments, one or more other therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. In some embodiments, a taxane compound is selectedfrom paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®,Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel(Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis),and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, one or more other therapeutic agent is a nucleosideinhibitor, or a therapeutic agent that interferes with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells.

In some embodiments, a nucleoside inhibitor is selected from trabectedin(guanidine alkylating agent, Yondelis®, Janssen Oncology),mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals);vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals;Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®,Merck); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb;Gleostine®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, Vidaza®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi(enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine(bifunctional mechlorethamine derivative, believed to form interstrandDNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

In some embodiments, one or more other therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib(Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib(Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AGand Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®,Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®,Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis);nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®,BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib(Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®,Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib(Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib(Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, suchas crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); andalectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaceuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TK1258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In another embodiment, the present invention provides a method oftreating organ transplant rejection or graft vs. host disease comprisingadministering to a patient in need thereof a provided compound and oneor more additional therapeutic agents selected from a steroid,cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTKinhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor,and a SYK inhibitor.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a BTK inhibitor,wherein the disease is selected from inflammatory bowel disease,arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathicthrombocytopenic purpura (ITP), rheumatoid arthritis, psoriaticarthritis, osteoarthritis, Still's disease, juvenile arthritis,diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiplesclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barresyndrome, acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipidantibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmunegastritis, pernicious anemia, celiac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behcet's disease,chronic fatigue, dysautonomia, membranous glomerulonephropathy,endometriosis, interstitial cystitis, pemphigus vulgaris, bullouspemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferativedisease, rejection of transplanted organs or tissues, AcquiredImmunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes,graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma,allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferativedisorder, e.g., diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,multiple myeloma (also known as plasma cell myeloma), non-Hodgkin'slymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone Bcell lymphoma, nodal marginal zone B cell lymphoma, mantle celllymphoma, mediastinal (thymic) large B cell lymphoma, intravascularlarge B cell lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer,prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mastcell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer,colorectal cancer, pancreatic cancer, diseases of the bone and jointsincluding, without limitation, rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome,systemic sclerosis, osteoporosis, bone cancer, bone metastasis, athromboembolic disorder, (e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, deep venous thrombosis), inflammatory pelvicdisease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis,meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,gastritis, enteritis, dermatitis, gingivitis, appendicitis,pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy,Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren'sdisease, tissue graft rejection, hyperacute rejection of transplantedorgans, asthma, allergic rhinitis, chronic obstructive pulmonary disease(COPD), autoimmune polyglandular disease (also known as autoimmunepolyglandular syndrome), autoimmune alopecia, pernicious anemia,glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma,vasculitis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson'sdisease, Alzheimer's disease, diabetes, septic shock, systemic lupuserythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenilearthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleraderma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from a cancer, a neurodegenativedisorder, an angiogenic disorder, a viral disease, an autoimmunedisease, an inflammatory disorder, a hormone-related disease, conditionsassociated with organ transplantation, immunodeficiency disorders, adestructive bone disorder, a proliferative disorder, an infectiousdisease, a condition associated with cell death, thrombin-inducedplatelet aggregation, chronic myelogenous leukemia (CML), chroniclymphocytic leukemia (CLL), liver disease, pathologic immune conditionsinvolving T cell activation, a cardiovascular disorder, and a CNSdisorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from benign or malignant tumor,carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments, one or more other therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, aPI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib(BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib(GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib(formerly IPI-145, Infinity Pharmaceuticals); PQR309 (PiqurTherapeutics, Switzerland); and TGR1202 (formerly RP5230, TGTherapeutics).

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms fortopical ortransdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity or degading a protein kinase in abiological sample comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

According to another embodiment, the invention relates to a method ofinhibiting or degrading STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6, or a mutant thereof, activity in a biological sample comprisingthe step of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition and/or degradation of a STAT protein, or a protein selectedfrom STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6, or a mutantthereof, activity in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

Another embodiment of the present invention relates to a method ofdegrading a protein kinase and/or inhibiting protein kinase activity ina patient comprising the step of administering to said patient acompound of the present invention, or a composition comprising saidcompound.

According to another embodiment, the invention relates to a method ofdegrading and/or inhibiting one or more of STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6, or a mutant thereof, activity in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. In otherembodiments, the present invention provides a method for treating adisorder mediated by one or more of STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6, or a mutant thereof, in a patient in need thereof,comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name Aromasin™. Formestane is marketed under the trade nameLentaron™. Fadrozole is marketed under the trade name Afema™.Anastrozole is marketed under the trade name Arimidex™. Letrozole ismarketed under the trade names Femara™ or Femar™. Aminoglutethimide ismarketed under the trade name Orimeten™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

In some embodiments, one or more other therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®,Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®,Pfizer).

In some embodiments, one or more other therapeutic agent is an aromataseinhibitor. In some embodiments, an aromatase inhibitor is selected fromexemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) andletrozole (Femara®, Novartis).

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™ Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™) The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™ Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof, see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporne derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aPI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C1-1033, EKB-569, GW-2016, ELI,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

In some embodiments, one or more other therapeutic agent is a growthfactor antagonist, such as an antagonist of platelet-derived growthfactor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (Erbitux®,Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®,Amgen); and osimertinib (targeting activated EGFR, Tagrisso®,AstraZeneca).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777 (Zamestra™).The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, such as telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™); carfilzomib(Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-O-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, especiallythe lactate salt. Somatostatin receptor antagonists as used herein referto compounds which target, treat or inhibit the somatostatin receptorsuch as octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12- 281(Asta Medica), CDC-801 (Celgene), SeICID™CC-10004 (Celgene), VM554/UM565(Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists;A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol(salbutamol), metaproterenol, terbutaline, salmeterol fenoterol,procaterol, and especially, formoterol and pharmaceutically acceptablesalts thereof. Suitable bronchodilatory drugs include anticholinergic orantimuscarinic compounds, in particular ipratropium bromide, oxitropiumbromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is provided for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIRI, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13/69264; WO14/036357).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446;WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), andMSB0010718C (WO2013/79174).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570,WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166 (WO11/028683).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS.F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919(WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MEDI4736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1 h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June; hereby incorporated byreference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+(Th17) and CD8+(Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORyt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORyt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams et al., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiments, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams et al. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. Adamset al.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the contents of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodiments, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BiTE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BiTE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BiTE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BiTE®-activated T cells. In some embodiment, the bystander cellscomprises tumor-associated antigen (TAA) negative cancer cells. In someembodiment, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex-vivo expanded tumor-infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺(αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2,B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors includeantibodies, or antigen binding fragments thereof, other bindingproteins, biologic therapeutics, or small molecules, that bind to andblock or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1,BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049.Illustrative immune checkpoint inhibitors include Tremelimumab (CTLA-4blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1;MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011(anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4checkpoint inhibitor). Checkpoint protein ligands include, but are notlimited to PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, insolidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

In some embodiments, STAT3 inhibition/degradation can significantlyenhance CDN-induced STING signaling and antitumor immunity (Pei et al.,Can. Lett. 2019, 450:110).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION Abbreviations

-   -   Ac: acetyl    -   AcOH: acetic acid    -   ACN: acetonitrile    -   Ad: adamantly    -   AIBN: 2,2′-azo bisisobutyronitrile    -   Anhyd: anhydrous    -   Aq: aqueous    -   B₂Pin₂: bis        (pinacolato)diboron-4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)    -   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   BH₃: Borane    -   Bn: benzyl    -   Boc: tert-butoxycarbonyl    -   Boc₂O: di-tert-butyl dicarbonate    -   BPO: benzoyl peroxide    -   ^(n)BuOH: n-butanol    -   CDI: carbonyldiimidazole    -   COD: cyclooctadiene    -   d: days    -   DABCO: 1,4-diazobicyclo[2.2.2]octane    -   DAST: diethylaminosulfur trifluoride    -   dba: dibenzylideneacetone    -   DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene    -   DCE: 1,2-dichloroethane    -   DCM: dichloromethane    -   DEA: diethylamine    -   DHP: dihydropyran    -   DIBAL-H: diisobutylaluminum hydride    -   DIPA: diisopropylamine    -   DIPEA or DIEA: N,N-diisopropylethylamine    -   DMA: N,N-dimethylacetamide    -   DME: 1,2-dimethoxyethane    -   DMAP: 4-dimethylaminopyridine    -   DMF: N,N-dimethylformamide    -   DMP: Dess-Martin periodinane    -   DMSO-dimethyl sulfoxide    -   DPPA: diphenylphosphoryl azide    -   dppf: 1,1′-bis(diphenylphosphino)ferrocene    -   EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride    -   ee: enantiomeric excess    -   ESI: electrospray ionization    -   EA: ethyl acetate    -   EtOAc: ethyl acetate    -   EtOH: ethanol    -   FA: formic acid    -   h or hrs: hours    -   HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   HCl: hydrochloric acid    -   HPLC: high performance liquid chromatography    -   HOAc: acetic acid    -   IBX: 2-iodoxybenzoic acid    -   IPA: isopropyl alcohol    -   KHMDS: potassium hexamethyldisilazide    -   K₂CO₃: potassium carbonate    -   LAH: lithium aluminum hydride    -   LDA: lithium diisopropylamide    -   m-CPBA: meta-chloroperbenzoic acid    -   M: molar    -   MeCN: acetonitrile    -   MeOH: methanol    -   Me₂S: dimethyl sulfide    -   MeONa: sodium methylate    -   Mel: iodomethane    -   min: minutes    -   mL: milliliters    -   mM: millimolar    -   mmol: millimoles    -   MPa: mega pascal    -   MOMCl: methyl chloromethyl ether    -   MsCl: methanesulfonyl chloride    -   MTBE: methyl tert-butyl ether    -   nBuLi: n-butyllithium    -   NaNO₂: sodium nitrite    -   NaOH: sodium hydroxide    -   Na₂SO₄: sodium sulfate    -   NBS: N-bromosuccinimide    -   NCS: N-chlorosuccinimide    -   NFSI: N-Fluorobenzenesulfonimide    -   NMO: N-methylno&rpholine N-oxide    -   NMP: N-methylpyrrolidine    -   NMR: Nuclear Magnetic Resonance    -   ° C.: degrees Celsius    -   Pd/C: Palladium on Carbon    -   Pd(OAc)₂: Palladium Acetate    -   PBS: phosphate buffered saline    -   PE: petroleum ether    -   POCl₃: phosphorus oxychloride    -   PPh₃: triphenylphosphine    -   PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate    -   Rel: relative    -   R.T. or rt: room temperature    -   sat: saturated    -   SEMCl: chloromethyl-2-trimethylsilylethyl ether    -   SFC: supercritical fluid chromatography    -   SOCl₂: sulfur dichloride    -   tBuOK: potassium tert-butoxide    -   TBAB: tetrabutylammonium bromide    -   TBAI: tetrabutylammonium iodide    -   TEA: triethylamine    -   Tf: trifluoromethanesulfonate    -   TfAA, TFMSA or Tf₂O: trifluoromethanesulfonic anhydride    -   TFA: trifluoracetic acid    -   TIPS: triisopropylsilyl    -   THF: tetrahydrofuran    -   THP: tetrahydropyran    -   TLC: thin layer chromatography    -   TMEDA: tetramethylethylenediamine    -   pTSA: para-toluenesulfonic acid    -   wt: weight    -   Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

All reactions are carried out under nitrogen or argon unless otherwisestated.

Proton NMR (¹H NMR) is conducted in deuterated solvent. In certaincompounds disclosed herein, one or more ¹H shifts overlap with residualproteo solvent signals; these signals have not been reported in theexperimental provided hereinafter.

TABLE 2 Analytical instruments LCMS Shimadzu UFLC MS: LCMS-2020 AgilentTechnologies 1200 series MS: Agilent Technologies 6110 AgilentTechnologies 1200 series MS: LC/MSD VL NMR BRUKER AVANCE III/400;Frequency (MHz) 400.13; Nucleus: 1H; Number of Transients: 8 Prep-HPLCGilson GX-281 systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F,GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra Analytical AgilentTechnologies 1290 Infinity cSFC Prep-cSFC Waters SFC Prep 80

For acidic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with ChromolithFlash RP-18e 25*2.0 mm, eluting with 0.0375 vol % TFA in water (solventA) and 0.01875 vol % TFA in acetonitrile (solvent B). Other LCMS wasrecorded on an Agilent 1290 Infinity RRLC attached with Agilent 6120Mass detector. The column used was BEH C18 50*2.1 mm, 1.7 micron. Columnflow was 0.55 ml/min and mobile phase were used (A) 2 mM AmmoniumAcetate in 0.1% Formic Acid in Water and (B) 0.1% Formic Acid inAcetonitrile.

For basic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS 2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with Xbridge C18,2.1×50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C182.1×30 mm columns packed with 5 mm C18-coated silica, eluting with 0.05vol % NH₃.H₂O in water (solvent A) and acetonitrile (solvent B).

HPLC Analytical Method: HPLC was carried out on X Bridge C18 150*4.6 mm,5 micron. Column flow was 1.0 ml/min and mobile phase were used (A) 0.1%Ammonia in water and (B) 0.1% Ammonia in Acetonitrile.

Prep HPLC Analytical Method: The compound was purified on ShimadzuLC-20AP and UV detector. The column used was X-BRIDGE C18 (250*19)mm, 5.Column flow was 16.0 ml/min. Mobile phase were used (A) 0.1% Formic Acidin Water and (B) Acetonitrile Basic method used (A) 5 mM ammoniumbicarbonate and 0.1% NH3 in Water and (B) Acetonitrile or (A) 0.1%Ammonium Hydroxide in Water and (B) Acetonitrile. The UV spectra wererecorded at 202 nm & 254 nm.

NMR Method: The 1H NMR spectra were recorded on a Bruker Ultra ShieldAdvance 400 MHz/5 mm Probe (BBFO). The chemical shifts are reported inpart-per-million.

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Intermediates Tert-butyl N-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate (IntermediateA)

Step 1. Methyl(2R,3R)-3-[(4-bromophenyl)methoxy]-2-[[(tert-butoxy)carbonyl]amino]butanoate.To a solution of methyl(2R,3R)-2-[[(tert-butoxy)carbonyl]amino]-3-hydroxybutanoate (11.7 g,50.2 mmol) and 1-bromo-4-(bromomethyl)benzene (15.1 g, 60.2 mmol) in DCM(80 mL) were added silver oxide (17.4 g, 75.2 mmol) and n-hexane (10 mL)at room temperature under nitrogen atmosphere. The resulting mixture wasstirred for 3 hours at 60° C. under nitrogen atmosphere. The reactionmixture was cooled down to room temperature and filtered. The filteredcake was washed with DCM (3×80 mL). The combined filtrates wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with 10% ethyl acetate in petroleumether to afford the title compound as a light yellow oil (7.30 g, 35%):¹H NMR (400 MHz, CDCl₃) δ 7.48-7.41 (m, 2H), 7.19 (d, J=8.1 Hz, 2H),5.28 (d, J=8.9 Hz, 1H), 4.55 (dd, J=9.0, 3.9 Hz, 1H), 4.51 (s, 2H), 3.83(td, J=6.4, 4.0 Hz, 1H), 3.75 (s, 3H), 1.44 (s, 9H), 1.22 (d, J=6.4 Hz,3H); MS (ESI, m/z): [(M+1)]⁺=402.15, 404.15.

Step 2. Tert-butylN-[(2S,3R)-3-[(4-bromophenyl)methoxy]-1-hydroxybutan-2-yl]carbamate. Toa solution of methyl(2R,3R)-3-[(4-bromophenyl)methoxy]-2-[[(tert-butoxy)carbonyl]amino]butanoate(7.00 g, 17.4 mmol) in THF (20 mL) was added LiBH₄ (2 M solution in THF,17.5 mL, 538 mmol) at room temperature under nitrogen atmosphere. Theresulting solution was stirred for 16 hours at room temperature undernitrogen atmosphere. The resulting mixture was diluted with water (200mL) and extracted with ethyl acetate (3×60 mL). The combined organiclayers was washed with brine (100 mL) and dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith 30% ethyl acetate in petroleum ether to afford the title compoundas a light yellow oil (6.50 g, 95%): ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.45(m, 2H), 7.22-7.17 (m, 2H), 5.37-5.26 (m, 1H), 4.58 (d, J=11.9 Hz, 1H),4.37 (d, J=11.9 Hz, 1H), 3.97 (dd, J=11.5, 3.5 Hz, 1H), 3.85-3.76 (m,1H), 3.64 (dd, J=11.5, 3.7 Hz, 1H), 3.60-3.52 (m, 1H), 2.81 (s, 1H),1.44 (s, 9H), 1.26 (dd, J=6.8, 2.2 Hz, 3H); MS (ESI, m/z):[(M+23)]⁺=396.20, 398.20.

The following intermediates in Table 3 were prepared according to Step 2of the procedure to prepare Intermediate A.

TABLE 3 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A-2-1

tert-butyl N-(2S, 3R)-3-[(tert- butyldimethylsilyl) oxy]-1-hydroxybutan-2- yl]carbamate 320.15 (400 MHz, CDCl₃) δ 5.40 (d, J = 8.1Hz, 1H), 4.24-4.15 (m, 1H), 4.17-4.09 (m, 1H), 3.63 (dd, J = 11.6, 3.4Hz, 1H), 3.45-3.38 (m, 1H), 1.47 (s, 9H), 1.26 (d, J = 6.4 Hz, 3H), 0.91(s, 9H), 0.11 (s, 6H) A-2-2

tert-butyl N- [(2S,3R)-3-(3- bromophenoxy)-1- hydroxybutan-2-yl]carbamate 360.00, 362.00 (400 MHz, DMSO-d₆) δ 7.23 (t, J = 8.0 Hz,1H), 7.13-7.07 (m, 2H), 6.95-6.89 (m, 1H), 6.64 (d, J = 9.2 Hz, 1H),4.71 (t, J = 5.4 Hz, 1H), 4.53-4.47 (m, 1H), 3.73-3.67 (m, 1H),3.49-3.42 (m, 2H), 1.39 (s, 9H), 1.20 (d, J = 6.3 Hz, 3H) A-2-3

[4-[(tert- butyldiphenylsilyl) oxy]cyclohexyl] methanol N/A (400 MHz,CDCl₃) δ 7.75-7.65 (m, 4H), 7.46-7.37 (m, 6H), 3.62-3.55 (m, 1H), 3.39(d, J = 6.4 Hz, 2H), 1.89 (dd, J = 13.4, 3.8 Hz, 2H), 1.72 (d, J = 13.4Hz, 2H), 1.46-1.39 (m, 4H), 1.08 (s, 9H), 0.89-0.78 (m, 2H)

Step 3. Tert-butylN-[(2R,3R)-3-[(4-bromophenyl)methoxy]-1-oxobutan-2-yl]carbamate. To amixture of tert-butyl N-[(2S,3R)-3-[(4-bromophenyl)methoxy]-1-hydroxybutan-2-yl]carbamate (6.50 g, 17.4mmol) in DCM (200 mL) was added DMP (9.58 g, 22.6 mmol) in portions atroom temperature under nitrogen atmosphere. After stirring foradditional 2 hours, the resulting mixture was filtered. The filteredcake was washed with DCM (2×10 mL). The combined filtrates wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with 10% ethyl acetate in petroleumether to afford the title compound as a light yellow oil (5.30 g, 740%):¹H NMR (400 MHz, CDCl₃) δ 9.77 (s, 1H), 7.52-7.41 (m, 2H), 7.22-7.09 (m,2H), 5.39 (d, J=7.3 Hz, 1H), 4.55 (d, J=11.9 Hz, 1H), 4.42 (d, J=12.0Hz, 1H), 4.33 (dd, J=7.2, 3.9 Hz, 1H), 3.92 (qd, J=6.6, 4.4, 2.6 Hz,1H), 1.45 (s, 9H), 1.40 (d, J=6.6 Hz, 3H); MS (ESI, m/z):[(M−1)]⁺=371.00, 373.00.

The intermediates in Table 4 were prepared according to Step 3 of theprocedure to prepare Intermediate A.

TABLE 4 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A-3-1

tert-butyl N-[(2R, 3R)-3-R[(tert- butyldimethylsilyl) oxy]-1-oxobutan-2-yl]carbamate 318.20 (400 MHz, CDCl₃) δ 9.81 (s, 1H), 5.43 (s, 1H),4.21 (s, 2H), 1.48 (s, 9H), 0.94 (d, J = 2.6 Hz, 3H), 0.91 (t, J = 4.0Hz, 1H), 0.87 (s, 9H), 0.09 (s, 6H) A-3-2

methyl (S)-4- ((tert- butoxycarbonyl) amino)-5- oxopentanoate 246.13(400 MHz, CDCl₃) δ 9.63 (s, 1H), 5.25-5.22 (m, 1H), 4.33-4.30 (m, 1H),3.73 (s, 3H), 2.57-2.39 (m, 2H), 2.34-2.30 (m, 1H), 1.98-1.88 (m, 1H),1.49 (s, 9H). A-3-3

benzyl 4- formylcyclohexane- 1-carboxylate 247.13 (400 MHz, Chloroform-d) δ 9.68 (s, 1H), 7.43- 7.30 (m, 5H), 5.14 (d, J = 4.6 Hz, 2H), 2.52(p, J = 6.1 Hz, 1H), 2.38 (tt, J = 6.5, 4.9 Hz, 1H), 1.99 (dq, J = 12.1,5.6 Hz, 2H), 1.86-1.68 (m, 4H), 1.68-1.51 (m, 2H) A-3-4

3-[(tert- butyldiphenylsilyl) oxy]cyclobutane- 1-carbaldehyde N/A (400MHz, Methanol-d₄) δ 7.71-7.62 (m, 4H), 7.50-7.34 (m, 6H), 4.40 (d, J =6.0 Hz, 1H), 4.14- 4.02 (m, 1H), 2.47-2.30 (m, 1H), 2.32-2.09 (m, 2H),2.05-1.72 (m, 2H), 1.04 (s, 9H) A-3-5

tert-butyl N- [(2R,3R)-3-(3- bromophenoxy)-1- oxobutan-2- yl]carbamate[(M − 1)]⁻ = 356.05, 358.05 (400 MHz, DMSO-d₆) δ 9.59 (s, 1H), 7.51 (d,J = 7.6 Hz, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.19-7.06 (m, 2H), 6.96 (d, J= 8.5 Hz, 1H), 4.90-4.83 (m, 1H), 4.29-4.13 (m, 1H), 1.41 (s, 9H), 1.27(d, J = 6.4 Hz, 3H) A-3-6

4-[(tert- butyldiphenylsilyl) oxy]cyclohexane- 1-carbaldehyde N/A (400MHz, DMSO-d₆) δ 9.50 (s, 1H), 7.64-7.52 (m, 4H), 7.52-7.35 (m, 6H),3.64-3.58 (m, 1H), 2.26-2.18 (m, 1H), 1.91- 1.67 (m, 4H), 1.45-1.30 (m,2H), 1.23-1.06 (m, 2H), 1.01 (s, 9H)

Step 4. Methyl(2E,4S,5R)-5-[(4-bromophenyl)methoxy]-4-[[(tert-butoxy)carbonyl]amino]hex-2-enoate.To a solution of tert-butylN-[(2R,3R)-3-[(4-bromophenyl)methoxy]-1-oxobutan-2-yl]carbamate (20.3 g,54.5 mmol) in DCM (350 mL) was added methyl2-(triphenyl-lambda5-phosphanylidene)acetate (20.1 g, 60.0 mmol) at roomtemperature under nitrogen atmosphere. After stirring for 16 hours atroom temperature, the resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with 5% ethyl acetate in petroleum ether. Desired fractions werecollected and concentrated under reduced pressure to afford the titlecompound as a white solid (20.5 g, 85%): ¹H NMR (400 MHz, CDCl₆) δ 8.73(s, 1H), 7.24 (d, J=7.8 Hz, 2H), 7.17 (d, J=7.7 Hz, 2H), 6.94-6.86 (m,2H), 6.73 (d, J=8.0 Hz, 1H), 4.81-4.78 (m, 1H), 4.45-4.42 (m, 1H), 4.33(t, J=4.7 Hz, 2H), 4.26-4.21 (m, 1H), 3.92-3.88 (s, 4H), 3.81 (s, 5H),3.58-3.53 (m, 4H), 3.47-3.41 (m, 3H), 2.80-2.54 (m, 7H), 1.88 (s, 5H),1.27 (s, 3H); MS (ESI, m/z): [(M+23)]⁺=450.20, 452.20.

The intermediates in Table 5 were prepared according to Step 4 of theprocedure to prepare Intermediate A.

TABLE 5 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A-4-1

methyl (2E,4S, 5R)-4-[(tert- butoxycarbonyl) amino]-5-[(tert-butyldimethylsilyl) oxy]hex-2-enoate 374.25 (400 MHz, CDCl₃) δ 6.94 (dd,J = 15.7, 6.6 Hz, 1H), 5.99 (d, J = 15.7 Hz, 1H), 4.84 (d, J = 8.9 Hz,1H), 4.18 (d, J = 7.5 Hz, 1H), 3.97 (s, 1H), 3.76 (s, 3H), 1.46 (s, 9H),1.15 (d, J = 6.3 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 6H) A-4-2

methyl (1r,4r)-4- ((E)-3-(tert- butoxy)-3- oxoprop-1-en-1-yl)cyclohexane-1- carboxylate N/A (400 MHz, DMSO-d₆) δ 6.73 (dd, J =15.7, 6.7 Hz, 1H), 5.69 (dd, J = 15.7, 1.4 Hz, 1H), 3.59 (s, 3H),2.29-2.25 (m, 1H), 2.14-2.10 (m, 1H),1.98-1.88 (m, 2H), 1.81-1.74 (m,2H), 1.43 (s, 9H), 1.38-1.34 (m, 2H), 1.18-1.14 (m, 2H). A-4-3

tert-butyl 2-(4- methylenecyclohexyl) acetate N/A (300 MHz, CDCl3) δ4.63 (s, 2H), 2.33-2.30 (m, 2H), 2.14 (d, J = 7.0 Hz, 2H), 2.7-2.04 (m,2H), 2.00-1.77 (m, 3H), 1.47 (s, 9H), 1.18-1.01 (m, 2H). A-4-4

methyl (2E,4S,5R)-5-(3- bromophenoxy)-4- [(tert- butoxycarbonyl)amino]hex-2-enoate 414.05, 416.05 (300 MHz, DMSO-d6) δ 7.37-7.20 (m,2H), 7.17-7.12 (m, 2H), 7.01-6.88 (m, 2H), 6.03 (dd, J = 15.7, 1.6 Hz,1H), 4.61-4.40 (m, 2H), 3.68 (s, 3H), 1.40 (s, 9H), 1.20 (d, J = 6.2 Hz,3H) A-4-5

tert-butyl (2E,4E)- 5-[3-[(tert- butyldiphenylsilyl) oxy]cyclobutyl]penta-2,4-dienoate N/A (400 MHz, Methanol-d4) δ 7.69-7.65 (m, 4H),7.48-7.36 (m, 6H), 7.20-7.11 (m, 1H), 6.16-6.11 (m, 1H), 5.75 (d, J =15.3 Hz, 1H), 4.21-4.13 (m, 1H), 2.39-2.33 (m, 3H), 1.99-1.86 (m, 1H),1.49 (s, 9H), 1.04 (s, 9H), 0.95-0.85 (m, 2H) A-4-6

methyl (4S)-4- [(tert- butoxycarbonyl) amino]hex-5-enoate 244.20 (400MHz, Chloroform-d) δ 5.76 (ddd, J = 17.2, 10.4, 5.6 Hz, 1H), 5.26-5.10(m, 2H), 4.56-4.53 (m, 1H), 4.21-4.04 (m, 1H), 3.69 (s, 3H), 2.40 (t, J= 7.6 Hz, 2H), 2.00-1.85 (m, 1H), 1.82-1.78 (m, 1H), 1.45 (s, 9H). A-4-7

ethyl (2E)-4-[3- (benzyloxy) cyclobutylidene] but-2-enoate [(M + Na)]+ =294.20 (400 MHz, DMSO-d6) δ 7.40-7.27 (m, 5H), 7.13 (dd, J = 15.3, 11.4Hz, 1H), 6.20-6.12 (m, 1H), 5.84 (d, J = 15.3 Hz, 1H), 4.43 (s, 2H),4.12 (q, J = 7.1 Hz, 2H), 3.26-3.11 (m, 1H), 3.07-2.94 (m, 1H),2.79-2.74 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). A-4-8

8-methylidene- 1,4- dioxaspiro[4.5] decane N/A (400 MHz, CDCl3)4.71-4.67 (m, 2H), 4.02-3.97 (m, 4H), 2.33-2.28 (m, 4H), 1.76-1.70 (m,4H) A-4-9

ethyl (2E)-4-(4- oxocyclohexy- lidene)but-2-enoate N/A (300 MHz,DMSO-d₆) δ 7.56-7.47 (m, 1H), 6.25 (d, J = 11.7 Hz, 1H), 5.97 (d, J =15.1 Hz, 1H), 4.22-4.08 (m, 2H), 2.79-2.74 (m, 2H), 2.64-2.62 (m 2H),2.45-2.38 (m, 4H), 1.27-1.20 (m, 3H) A-4-10

tert-butyl (2E)-3- 4-[(tert- butyldiphenylsilyl) oxy]cyclohexyl]prop-2-enoate N/A (400 MHz, DMSO-d₆) δ 7.66-7.58 (m, 4H), 7.52-7.40 (m,6H), 6.65 (dd, J = 15.7, 6.9 Hz, 1H), 5.64 (dd, J = 15.8, 1.4 Hz, 1H),3.62-3.57 (m, 1H), 2.14-2.03 (m, 1H), 1.80 (d, J = 12.4 Hz, 2H), 1.65(d, J = 13.2 Hz, 2H), 1.40 (s, 9H), 1.05-0.98 (m, 12H), 0.89-0.83 (m,1H)

Step 5. Methyl(4S,5R)-5-[(4-bromophenyl)methoxy]-4-[[(tert-butoxy)carbonyl]amino]hexanoate.To a solution of methyl(2E,4S,3R)-5-[(4-bromophenyl)methoxy]-4-[[(tert-butoxy)carbonyl]amino]hex-2-enoate (20.0 g, 46.7 mmol) in THF (350 mL) was addedaluminum nickel alloy (4.00 g, 4.70 mmol, 10% w/w) at room temperatureunder nitrogen atmosphere. The mixture was purged with hydrogen for 3times and stirred for 16 hours under hydrogenation atmosphere (2 atm.)at room temperature. The resulting mixture was filtered. The filteredcake was washed with THF (3×100 mL). The combined filtrates wasconcentrated under reduced pressure to afford the title compound as alight yellow oil (19.0 g, 85%): ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.39 (m,2H), 7.19 (d, J=8.3 Hz, 2H), 4.70 (d, J=10.1 Hz, 1H), 4.56-4.49 (m, 1H),4.38 (dd, J=11.5, 6.3 Hz, 1H), 3.73 (s, 1H), 3.66 (s, 3H), 2.41-2.32 (m,2H), 1.95 (dtd, J=15.4, 7.9, 7.4, 3.1 Hz, 1H), 1.67 (tdd, J=14.4, 11.9,9.7, 7.0 Hz, 1H), 1.42 (d, J=4.1 Hz, 9H), 1.18 (dd, J=6.2, 3.9 Hz, 3H);MS (ESI, m/z): [(M+23)]⁺=452.20, 454.20.

The intermediates in Table 6 were prepared according to Step 5 of theprocedure to prepare Intermediate A.

TABLE 6 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A-5-1

methyl (4S,5R)-4- ((tert- butoxycarbonyl) amino)-5-((tert-butyldimethylsilyl) oxy)hexanoate 376.20 (400 MHz, CDCl₃) δ 4.58 (d, J =9.9 Hz, 1H), 3.95-3.88 (m, 1H), 3.70 (s, 3H), 3.47 (s, 1H), 2.50-2.32(m, 2H), 1.95 (p, J = 7.2 Hz, 1H), 1.70-1.60 (m, 1H), 1.45 (s, 9H), 1.15(d, J = 6.4 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 6H) A-5-2

methyl (1r,4r)-4- (3-(tert-butoxy)-3- oxopropyl) cyclohexane-1-carboxylate N/A (400 MHz, DMSO-d₆) δ 3.58 (s, 3H), 2.26-2.15 (m, 3H),1.92-1.84 (m, 2H), 1.76-1.68 (m, 2H), 1.41-1.39 (m, 11H), 1.37-1.24 (m,2H), 1.19-1.15 (m, 1H), 0.97-0.90 (m, 2H). A-5-3

tert-butyl 5-[3- [(tert- butyldiphenylsilyl) oxy]cyclobutyl] pentanoateN/A (400 MHz, DMSO-d₆) δ 7.61-7.59 (m, 4H), 7.46-7.40 (m, 6H), 4.09-4.02(m, 1H), 2.29-2.19 (m, 1H), 2.16-2.11 (m, 2H), 1.60-1.48 (m, 3H),1.47-1.40 (m, 2H), 1.38 (s, 9H), 1.37-1.19 (m, 3H), 1.18-1.08 (m, 2H),0.97 (s, 9H) A-5-4

ethyl 4-(3- hydroxycyclobutyl) butanoate N/A (400 MHz, DMSO-d₆) δ 4.90(br, 1H), 4.16 (p, J = 6.7 Hz, 0.4 H), 4.05 (q, J = 7.1 Hz, 2H),3.90-3.81 (m, 0.6H), 2.34-2.21 (m, 3H), 2.18-1.96 (m, 1H), 1.94-1.79 (m,2H), 1.60-1.56 (m, 1H), 1.48- 1.27 (m, 4H), 1.18 (t, J = 7.1 Hz, 3H).A-5-5

ethyl 4-(4- oxocyclohexyl) butanoate N/A (400 MHz, DMSO-d₆) δ 4.09-4.04(m, 2H), 2.50-2.27 (m, 4H), 2.27-2.14 (m, 2H), 2.02-1.90 (m, 2H),1.79-1.65 (m, 1H), 1.65-1.52 (m, 2H), 1.40-1.23 (m, 4H), 1.21-1.17(m,3H) A-5-6

tert-butyl 3-[4- [(tert- butyldiphenylsilyl) oxylcyclohexyl] propanoateN/A (400 MHz, DMSO-d₆) δ 7.65-7.58 (m, 4H), 7.50-7.39 (m, 6H), 3.60-3.52(m, 1H), 2.12 (t, J = 7.7 Hz, 2H), 1.76 (d, J = 12.2 Hz, 2H), 1.60 (d, J= 13.1 Hz, 2H), 1.38 (s, 9H), 1.35-1.22 (m, 4H), 1.19-1.07 (m, 1H), 1.00(s, 9H), 0.79- 0.65 (m, 2H)

Step 6. Tert-butylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(Intermediate A). Methyl(4S,5R)-5-[(4-bromophenyl)methoxy]-4-[[(tert-butoxy)carbonyl]amino]hexanoate(13.8 g, 32.1 mmol) was added to a solution of 7 M NH₃ (g) in MeOH (120mL) at room temperature. The reaction mixture was sealed and stirred for16 hours at 90° C. The resulting mixture was cooled down to roomtemperature and concentrated under reduced pressure. The residue waspurified by reversed phase flash chromatography with the followingconditions: Column: WelFlash™ C18-I, 20-40 in, 330 g; Eluent A: water(plus 10 mmol/L NH₄HCO₃); Eluent B: ACN; Gradient: 35%-55% B in 25 min;Flow rate: 80 mL/min; Detector: UV 220/254 nm; desired fractions werecollected at 48% B and concentrated under reduced pressure to afford thetitle compound as a white solid (8.30 g, 630%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.52 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.23 (s, 1H),6.75-6.62 (m, 2H), 4.51-4.41 (m, 2H), 3.41 (tt, J=11.9, 6.7 Hz, 2H),2.04 (qdd, J=15.1, 9.7, 5.9 Hz, 2H), 1.77 (dt, J=6.9, 3.7 Hz, 1H), 1.48(ddd, J=14.2, 9.9, 5.4 Hz, 1H), 1.38 (s, 9H), 1.06 (d, J=6.1 Hz, 3H); MS(ESI, m/z): [(M+1)]⁺=415.15, 417.15.

The intermediates in Table 7 were prepared according to Step 6 of theprocedure to prepare Intermediate A.

TABLE 7 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A1

tert-butyl N- (3S,4R)-4-[tert- butyldimethylsilyl) oxyl-1-carbamoylpentan- 3-yl]carbamate 361.35 (400 MHz, CDCl₃) δ 6.36 (s, 1H),5.52 (s, 1H), 4.75 (d, J = 9.7 Hz, 1H), 3.90 (qd, J = 6.3, 3.4 Hz, 1H),3.57-3.45 (m, 1H), 2.37-2.17 (m, 2H), 2.00-1.87 (m, 1H), 1.64 (ddt, J =14.3, 12.2, 6.4 Hz, 1H), 1.45 (s, 9H), 1.14 (d, J = 6.3 Hz, 3H), 0.90(s, 9H), 0.07 (s, 6H) A2

tert-butyl N- [(3S,4R)-4-[(4- bromophenyl) methoxy]-1- (methylcarbamoyl)pentan-3- yl]carbamate 429.13, 431.13 (400 MHz, CDCl₃) δ 7.48 (d, J =8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.25 (s, 1H), 4.81 (d, J = 9.6Hz, 1H), 4.55 (d, J = 11.8 Hz, 1H), 4.38 (d, J = 11.8 Hz, 1H), 3.69-3.51(m, 2H), 2.82 (d, J = 4.7 Hz, 3H), 2.33-2.14 2H), 2.05- 1.90 (m, 1H),1.77-1.59 (m, 1H), 1.45 (s, 9H), 1.20 (d, J = 6.3 Hz, 3H) A51

(4S)-4-(5- bromopyridin-2- yl)-4[(2- methylpropane-2- sulfinyl)amino]butanamide 362.10, 364.10 (400 MHz, DMSO-d₆) δ 8.34-8.32 (d, J = 2.4 Hz,1H), 7.73-7.71 (m, 1H), 7.65- 7.63 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H),6.80 (s, 1H), 5.79-5.77 (d, J = 5.4 Hz, 1H), 4.34-4.29 (m, 1H),2.22-1.98 (m, 3H), 1.95-1.70 (m, 1H), 1.08 (s, 9H) A52

(4S)-4-(4- bromopyridin-2- y1)-4-[(2- methylpropane-2- sulfinyl)amino]butanamide 362.00, 364.00 (400 MHz, DMSO-d₆) δ 8.35 (d, J = 5.1 Hz, 1H),7.62 (s, 1H), 7.41 (dd, J = 5.1, 1.4 Hz, 1H), 7.31 (s, 1H), 6.85 (s,1H), 5.86 (d, J = 6.0 Hz, 1H), 4.32 (q, J = 6.5 Hz, 1H), 2.22-1.97 (m,3H), 1.91- 1.82 (m, 1H), 1.10 (s, 9H)

Tert-butylN-[(3S,4R)-4-[(3-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(Intermediate A3)

Step 1: Tert-butylN-[(3S,4R)-1-carbamoyl-4-hydroxypentan-3-yl]carbamate. To a solution oftert-butylN-[(3S,4R)-4-[(tert-butyldimethylsilyl)oxy]-1-carbamoylpentan-3-yl]carbamate(36.0 g, 99.8 mmol) in THF (720 mL) was added TBAF (31.3 g, 120 mmol) atroom temperature. After stirring for additional 16 h, the resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(50:1 to 10:1) to afford the title compound as a colorless solid (22.0g, 90%): ¹H NMR (400 MHz, CD₃OD) δ 6.45 (d, J=9.5 Hz, 1H), 3.64 (p,J=6.3 Hz, 1H), 3.45-3.33 (m, 1H), 2.36-2.17 (m, 2H), 2.03 (dtd, J=13.3,6.6, 3.4 Hz, 1H), 1.66-1.52 (m, 1H), 1.46 (s, 9H), 1.17 (d, J=6.4 Hz,3H); LC/MS (ESI, m/z): [(M+H)]⁺=247.25.

The intermediates in Table 8 were prepared according to step 1 of theprocedure to prepare Intermediate A3.

TABLE 8 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A3-1-1

tert-butyl (S)-(5- amino-1-((9- hydroxynon-2-yn- 1-yl)oxy)-5-oxopentan-2- yl)carbamate 371.20 (400 MHz, DMSO-d₆) δ 7.22 (s, 1H), 6.69(s, 1H), 6.63 (d, J = 8.6 Hz, 1H), 4.33 (t, J = 5.2 Hz, 1H), 4.09 (t, J= 2.1 Hz, 2H), 3.49 (d, J = 4.9 Hz, 1H), 3.38 (td, J = 6.5, 5.2 Hz, 2H),3.31- 3.26 (m, 2H), 2.23-2.18 (m, 2H), 2.07- 2.03 (m, 2H), 1.75-1.61 (m,2H), 1.43 (dd, J = 14.0, 7.0 Hz, 4H), 1.38(s, 9H), 1.36 -1.21 (m, 4H).A3-1-2

tert-butyl 3-(2- ethynylphenyl) propanoate N/A (400 MHz, DMSO-d₆) δ7.47-7.43 (m, 1H), 7.37-7.28 (m, 2H), 7.23 (td, J = 7.3, 1.8 Hz, 1H),4.39 (s, 1H), 2.97 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.37(s, 9H). A3-1-3

tert-butyl 5-(3- hydroxycyclobutyl) pentanoate N/A (400 MHz,Methanol-d₄) δ 4.07-3.96 (m, 1H), 2.44-2.37 (m, 2H), 2.24-2.20 (m, 2H),2.09-1.93 (m,1H), 1.76-1.63 (m, 1H), 1.63-1.52 (m, 2H), 1.49-1.40 (m,12H), 1.34-1.19 (m, 2H) A3-1-4

tert-butyl 4-(3- hydroxycyclobutyl) butanoate N/A (400 MHz, DMSO-d₆) δ4.87 (dd, J = 6.4, 1.6 Hz, 1H), 4.17-4.13 (m, 0.4H), 3.91-3.79 (m,0.6H), 2.36-2.20 (m, 1H), 2.18-2.13 (m, 2H), 2.06-1.80 (m, 2H),1.70-1.49 (m, 1H), 1.46-1.26 (m, 13H), 1.00-0.82 (m, 1H) A3-1-5

(2S,4R)-1-[(2S)- 3,3-dimethyl-2- [[1-(prop-2-yn-1- yl)cyclopropyl]formamido]butanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]methyl] pyrrolidine-2- carboxamide 537.25 (400 MHz,Methanol-d₄) δ 8.89 (s, 1H), 7.52-7.41 (m, 4H), 4.73 (s, 1H), 4.63-4.57(m, 2H), 4.55-4.50 (m, 1H), 4.38 (d, J = 15.4 Hz, 1H), 3.89 (d, J = 11.1Hz, 1H), 3.82 (dd, J = 11.0, 3.8 Hz, 1H), 2.87-2.81 (m, 1H), 2.57-2.48(m, 1H), 2.50 (s, 3H), 2.39 (dd, J = 17.9, 2.7 Hz, 1H), 2.30-2.16 (m,1H), 2.16-2.05 (m, 1H), 1.26-1.18 (m, 1H), 1.18-1.07 (m, 1H), 1.08 (s,9H), 0.90- 0.77 (m, 2H) A3-1-6

tert-butyl 3-(4- hydroxycyclohexyl) propanoate N/A (400 MHz, DMSO-d₆) δ4.44 (d, J = 4.5 Hz, 1H), 3.31-3.26 (m, 1H), 2.18 (t, J = 8.5 Hz, 2H),1.84-1.75 (m, 2H), 1.66 (d, J = 13.0 Hz, 2H), 1.40 (s, 9H), 1.37-1.35(m, 1H), 1.15-1.02 (m, 3H), 0.93-0.83 (m, 3H)

Step 2: Tert-butylN-[(3S,4R)-4-[(3-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(Intermediate A3). To a solution of tert-butylN-[(3S,4R)-1-carbamoyl-4-hydroxypentan-3-yl]carbamate (2.00 g, 8.12mmol) in DMF (30.0 mL) was added NaH (60% dispersion in mineral oil,0.34g, 8.53 mmol) at 0 TC. The reaction mixture was stirred at 0 TC for 1 h.To the above solution was added dropwise a solution of1-bromo-3-(bromomethyl) benzene (2.23 g, 8.93 mmol) in DMF (20.0 mL) at0 TC. The mixture was warmed slowly to room temperature and was stirredfor additional 2 h. The resulting solution was quenched with water (100mL), extracted with EtOAc (3×50.0 mL). The combined organic layers werewashed with brine (3×30.0 mL) and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by Prep-HPLC with the following conditions (Column:XBridge Shield RP18 OBD Column, 30×150 mm, 5 m; Mobile Phase A: water(plus 10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min;Gradient: (B %) 5%˜35% in 7 min; Detector: UV 220 nm). The fractionscontaining desired product were collected at 6.3 min and concentratedunder reduced pressure to afford the title compound as a colorless solid(1.20 g, 350%): ¹H NMR (400 MHz, DMSO-4) δ 7.53 (s, 1H), 7.46 (dt,J=7.6, 1.8 Hz, 1H), 7.35-7.26 (m, 2H), 7.24 (s, 1H), 6.73-6.63 (m, 2H),4.48 (s, 2H), 3.50 (p, J=7.4, 6.0 Hz, 1H), 3.42 (p, J=5.9 Hz, 1H), 2.06(qdd, J=15.1, 9.7, 6.0 Hz, 2H), 1.76 (dtd, J=13.7, 7.0, 6.6, 3.4 Hz,1H), 1.52-1.44 (m, 1H), 1.39 (s, 9H), 1.07 (d, J=6.2 Hz, 3H); LC/MS(ESI, m/z): [(M+H)]⁺=415.05, 417.05.

The intermediates in Table 9 were prepared according to Step 2 of theprocedure to prepare Intermediate A3.

TABLE 9 Characterization for intermediates prepared according to above.Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A4

tert-butyl N- [(3S,4R)-4-[(2- bromophenyl) methoxy]-1- carbamoylpentan-3-yl]carbamate 415.10, 417.10 (400 MHz, CD₃OD) δ 7.56 (td, J = 8.2, 1.5Hz, 2H), 7.35 (td, J = 7.5, 1.2 Hz, 1H), 7.20 (td, J = 7.7, 1.8 Hz, 1H),4.67 (d, J = 12.4 Hz, 1H), 4.58 (d, J = 12.4 Hz, 1H), 3.65-3.53 (m, 2H),2.39-2.17 (m, 2H), 2.09-1.90 (m, 1H), 1.64 (td, J = 9.8, 5.0 Hz, 1H),1.45 (s, 9H), 1.23 (d, J = 5.9 Hz, 3H). A5

tert-butyl N- [(3S,4R)-4-[(6- bromonaphthalen- 2-yl)methoxyl- 1-carbamoylpentan- 3-yl]carbamate 465.10, 467.10 (400 MHz, DMSO-d₆) δ 8.19(d, J = 2.0 Hz, 1H), 7.92-7.83 (m, 3H), 7.63 (dd, J = 8.7, 2.0 Hz, 1H),7.54 (dd, J = 8.6, 1.5 Hz, 1H), 7.24 (s, 1H), 6.73-6.63 (m, 2H),4.70-4.58 (m, 2H), 3.49 (s, 1H), 3.54-3.41 (m, 1H), 2.07 (qdd, J = 15.0,9.8, 5.9 Hz, 2H), 1.88-1.75 (m, 1H), 1.57-1.43 (m, 1H), 1.37 (s, 9H),1.11 (d, J = 5.9 Hz, 3H). A6

tert-butyl N- [(3S,4R)-1- carbamoyl-4- (prop-2-yn-1- yloxy)pentan-3-yl]carbamate 285.35 (400 MHz, DMSO-d₆) δ 7.22 (s, 1H), 6.68 (s, 1H),6.62 (d, J = 9.3 Hz, 1H), 4.21-4.07 (m, 2H), 3.48 (p, J = 6.2 Hz, 1H),3.37 (t, J = 2.4 Hz, 1H), 2.13-1.92 (m, 2H), 1.76 (dddd, J = 13.4, 9.8,6.2, 3.1 Hz, 1H), 1.48-1.40 (m, 1H), 1.39 (s, 9H), 1.03 (d, J = 6.2 Hz,3H). A7

tert-butyl ((2R,3S)-6- amino-2-((7- bromonaphthalen- 2-yl)methoxy)-6-oxohexan-3- yl)carbamate 465.07, 467.05 (400 MHz, DMSO-d₆) δ 8.16 (d,J = 2.0 Hz, 1H), 7.94-7.84 (m, 3H), 7.61 (dd, J = 8.7, 2.0 Hz, 1H), 7.52(dd, J = 8.4, 1.6 Hz, 1H), 7.25 (s, 1H), 6.77-6.64 (m, 2H), 4.75-4.57(m, 2H), 3.51-3.45 (m, 2H), 2.10-2.03 (m, 2H), 1.84-1.80 (m, 1H),1.54-1.50 (m, 1H), 1.36 (s, 9H), 1.11 (d, J = 5.9 Hz, 3H). A8

tert-butyl ((2R,3S)-6- amino-2-((5- bromonaphthalen- 2-yl)methoxy)-6-oxohexan-3- yl)carbamate 465.07, 467.05 (400 MHz, DMSO-d₆) δ 8.09 (d,J = 8.7 Hz, 1H), 7.98-7.92 (m, 2H), 7.85 (dd, J = 7.4, 1.0 Hz, 1H), 7.66(dd, J = 8.8, 1.7 Hz, 1H), 7.48-7.41 (m, 1H), 7.24 (s, 1H), 6.75-6.63(m, 2H), 4.74-4.64 (m, 2H), 3.52-3.47 (m, 2H), 2.09-2.05 (m, 2H),1.83-1.81 (m, 1H), 1.53-1.50 (m, 1H), 1.35 (s, 9H), 1.11 (d, J = 5.9 Hz,3H). A9

tert-butyl (S)-(5- amino-1-((4- bromobenzyl)oxy)- 5-oxopentan-2-yl)carbamate 401.00, 403.00 (400 MHz, DMSO-d₆) δ 7.56-7.51 (m, 2H),7.32-7.26 (m, 2H), 7.23 (s, 1H), 6.74-6.63 (m, 2H), 4.44 (s, 2H),3.59-3.54 (m, 1H), 3.33-3.29 (m, 2H), 2.08-2.04 (m, 2H), 1.72-1.68 1H),1.52-1.49 (m 1H), 1.38 (s, 9H). A10

tert-butyl (S)-(5- amino-5-oxo-1- (prop-2-yn-1- yloxy)pentan-2-yl)carbamate 271.10 (400 MHz, CDCl₃) δ 6.50 (s, 1H), 5.41 (s, 1H), 4.96(d, J = 8.9 Hz, 1H), 4.24 (s, 2H), 3.83-3.81 (m, 1H), 3.62-3.52 (m, 2H),2.46 (t, J = 2.4 Hz, 1H), 2.37 -2.27 (m, 2H), 1.92-1.88 (m, 1H),1.71-1.68 (m, 1H), 1.47 (s, 9H). A11

ethyl (S)-10-((5- amino-2-((tert- butoxycarbonyl) amino)-5-oxopentyl)oxy) decanoate 431.30 (400 MHz, CDCl₃) δ 6.73 (s, 1 H), 5.45(s, 1H), 5.02-4.99 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.79-3.76 (m, 1H),3.46-3.37 (m, 3H), 2.37-2.28 (m, 4H), 1.89-1.85 (m, 2H), 1.78-1.74 (m,2H), 1.65-1.61 (m, 2H), 1.58-1.54 (m, 1H), 1.47 (s, 9 H), 1.34-1.30 (m,10H), 1.28 (t, J = 7.1 Hz, 3H). A12

ethyl (S)-9-((5- amino-2-((tert- butoxycarbonyl) amino)-5-oxopentyl)oxy) nonanoate 417.30 (400 MHz, CDCl₃) δ 6.67 (s, 1 H), 5.67(s, 1H), 4.97-4.95 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.79-3.76 (m, 1H),3.58-3.45 (m, 2H), 3.27-3.23 (m, 1H), 2.26 (t, J = 7.3 Hz, 2H),2.15-1.97 (m, 1H), 1.84-1.61 (m, 2H), 1.59-1.43 (m, 6H), 1.38 (s, 9 H),1.27-1.24 (m, 8H), 1.28 (t, J = 7.1 Hz, 3H). A13

ethyl (S)-8-((5- amino-2-((tert- butoxycarbonyl) amino)-5-oxopentyl)oxy) octanoate 403.30 (400 MHz, CDCl₃) δ 4.15 (q, J = 7.1 Hz,2H), 3.47-3.38 (m, 3H), 2.39-2.21 (m, 5H), 2.10-2.04 (m, 1H), 1.89 (q, J= 7.2 Hz, 2H), 1.84-1.54 (m, 4H), 1.51 (d, J = 2.6 Hz, 1H), 1.47 (s,9H), 1.41-1.31 (m, 5H), 1.30-1.25 (t, J = 7.1 Hz, 3H) A14

tert-butyl N- [(3S,4R)-4- (benzyloxy)-1- carbamoylpentan- 3-yl]carbamate337.20 (400 MHz, DMSO-d₆) δ 7.44-7.15 (m, 6H), 6.75-6.51 (m, 2H),4.52-4.42 (m, 2H), 3.49-3.41 (m, 2H), 2.17-1.93 (m, 2H), 1.86-1.74 (m,1H), 1.56-1.43 (m, 1H), 1.39 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H) A15

tert-butyl N- [(3S,4R)-4-[(4- bromo-3- fluorophenyl) methoxy]-1-carbamoylpentan- 3-yl]carbamate 433.32, 435.32 (400 MHz, DMSO-d₆) δ 7.65(t, J = 7.7 Hz, 1H), 7.35 (dd, J = 10.0, 1.9 Hz, 1H), 7.22 (s, 1H), 7.13(dd, J = 8.2, 1.9 Hz, 1H), 6.73-6.64 (m, 2H), 4.58-4.37 (m, 2H),3.52-3.38 (m, 2H), 2.15-1.96 (m, 2H), 1.84-1.69 (m, 1H), 1.54-1.44 (m,1H), 1.49 (s, 9H), 1.07 (d, J = 6.1 Hz, 3H) A16

tert-butyl N- [(3S,4R)-4-[(4- bromo-2- fluorophenyl) methoxy]-1-carbamoylpentan- 3-yl]carbamate 433.10 435.10 (400 MHz, DMSO-d₆) δ 7.52(d, J = 9.6 Hz, 1H), 7.47-7.38 (m, 2H), 7.21 (s, 1H), 6.68-6.64 (m, 2H),4.50 (q, J = 12.3 Hz, 2H), 3.45-3.43 (m, 2H), 2.36-1.90 (m, 2H),1.77-1.75 (m, 1H), 1.49-1.46 (m, 1H), 1.37 (s, 9H), 1.07 (d, J = 5.5 Hz,3H). A17

tert-butyl N- [(2S)-1-([9-[(tert- butyldimethylsilyl) oxy]non-2-yn-1-yl]oxy)-4- carbamoylbutan- 2-yl]carbamate 485.35 (400 MHz, DMSO-d₆) δ7.22 (s, 1H), 6.69 (s, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.23 (t, J = 6.6Hz, 1H), 4.09 (t, J = 2.1 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.35- 3.28(m, 4H), 2.22-2.18 (m, 2H), 2.08- 2.02 (m, 2H), 1.67-1.64 (m, 1H), 1.55-1.35 (s, 16H), 0.86 (s, 9H), 0.03 (s, 6H). A21

tert-butyl N- [(3S,4R)-4-[(4- bromo-3- methylphenyl) methoxy]-1-carbamoylpentan- 3-yl]carbamate 429.10, 431.10 (400 MHz, DMSO-d₆) δ 7.52(d, J = 8.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.23- 7.19 (m, 1H), 7.09(dd, J = 8.1, 2.2 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J = 9.2 Hz, 1H),4.48-4.36 (m, 2H), 3.47-3.38 (m, 2H), 2.34 (s, 3H), 2.05 (s, 1H),2.15-1.95 (m, 1H), 1.78-1.76 (m, 1H), 1.49-1.46 (m, 1H), 1.38 (s, 9H),1.06 (d, J = 6.1 Hz, 3H) A22

tert-butyl N- [(3S,4R)-4-[(4- bromo-2- fluorophenyl) methoxy]-1-carbamoylpentan- 3-yl]carbamate 433.10 435.10 (400 MHz, DMSO-d₆) δ 7.52(d, J = 9.6 Hz, 1H), 7.47-7.37 (m, 2H), 7.21 (s, 1H), 6.68 (s 1H) 6.61(d, J = 8.7 Hz, 1H), 4.50 (q, J = 12.3 Hz, 2H), 3.43 (d, J = 6.3 Hz,2H), 2.11-1.93 (m, 2H), 1.79-1.71 (m, 1H), 1.48-1.43 (m, 1H), 1.37 (s,9H), 1.35 (s, 1H), 1.07 (d, J = 5.5 Hz, 3H) A23

tert-butyl N- [(3S,4R)-4-[(4- bromo-2- methylphenyl) methoxy]-1-carbamoylpentan- 3-yl]carbamate 431.10, 433.10 (400 MHz, Methanol-d₄) δ7.35 (s, 1H), 7.28 (q, J = 8.2 Hz, 2H), 4.60-4.43 (m, 2H), 3.61-3.51 (m,2H), 2.34 (s, 3H), 2.31-2.16 (m, 2H), 2.02-1.84 (m, 1H), 1.69-1.53 (m,1H), 1.45 (s, 9H), 1.20 (d, J = 6.1 Hz, 3H)

Tert-butyl N-[(2S)-1-(4-bromophenoxy)-4-carbamoylbutan-2-yl]carbamate(Intermediate A18)

To a stirred solution of 4-bromophenol (968 mg, 5.59 mmol) in THF (45.0mL) were added PPh₃ (1.69 g, 6.44 mmol) and DEAD (1.12 g, 6.43 mmol)dropwise at 0° C. under nitrogen atmosphere. To the above mixture wasadded tert-butyl N-[(25)-4-carbamoyl-1-hydroxybutan-2-yl]carbamate (1.00g, 4.31 mmol) at room temperature. The resulting mixture was stirred foradditional 6 h at room temperature. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by reversephase flash chromatography with the following conditions: Column:WelFlash™ C18-I, 20-40 um, 80 g; Eluent A: water (plus 10 mmol/L FA);Eluent B: ACN; Gradient: 35%-60% B in 25 mi; Flow rate: 80 mL/min;Detector: UV 220/254 nm; desired fractions were collected at 5100 B andconcentrated under reduced pressure to afford the title compound as alight yellow solid (350 mg, 21H): ¹H NMR (400 MHz, DMSO-d₆) δ 7.47-7.41(m, 2H), 7.26 (s, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J=8.5 Hz, 1H), 6.73(s, 1H), 3.94-3.77 (m, 2H), 3.77-3.65 (m, 1H), 2.18-2.04 (m,2H),1.87-1.74 (m, 1H), 1.64-1.50 (m, 1H), 1.39 (s, 9H); LC/MS (ESI,m/z): [(M+1)]⁺=386.95, 388.95

The intermediates in Table 10 were prepared according to the aboveprocedure to prepare intermediate A 18.

TABLE 10 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A19

tert-butyl N- [(2S)-1-(3- bromo-2- fluorophenoxy)- 4- carbamoylbutan-2-yl]carbamate 405.26 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H), 7.26-7.17 (m,2H), 7.09 (td, J = 8.2, 1.7 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.74 (s,1H), 3.41-3.97 (m, 2H), 3.77-3.73 (m, 1H), 2.21-2.04 (m, 2H), 1.87-1.72(m, 1H), 1.69-1.52 (m, 1H), 1.38 (s, 9H) A20

tert-butyl N- [(2S)-1-(3- bromophenoxy)- 4- carbamoylbutan-2-yl]carbamate (800 mg, 23.99%) as a light yellow oil 387.00, 388.95(400 MHz, DMSO-d₆) δ 7.24 (t, J = 8.0 Hz, 2H), 7.15-7.11 (m, 2H), 6.97-6.93 (m, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 4.23 (t, J = 6.6Hz, 1H), 3.92-3.87 (m, 2H), 3.70 (d, J = 11.8 Hz, 1H), 2.12 (q, J = 6.7Hz, 2H), 1.80 (d, J = 14.8 Hz, 1H), 1.39 (s, 9H) A24

tert-butyl N- [(2S)-4- carbamoyl-1-(4- chloro-3- iodophenoxy) butan-2-yl]carbamate [(M − 1)]⁻ = 467.10 (300 MHz, DMSO-d₆) δ 7.67-7.51 (m, 1H),7.44 (d, J = 10.7 Hz, 1H), 7.23 (d, 1H), 6.99 (d, J = 8.9 Hz, 1H), 6.80(d, J = 8.4 Hz, 1H), 6.70 (d, 1H), 3.87 (m, J = 5.9 Hz, 2H), 3.30 (m,1H), 2.52-2.49 (m, J = 1.9 Hz, 8H), 1.75-1.71 (m, 1H), 1.61-1.57 (m,1H), 1.26-1.22 (m, 1H), 0.96-0.78 (m, 2H) A25

tert-butyl N- [(2S)-1-(5- bromo-2- chlorophenoxy)- 4- carbamoylbutan-2-yl]carbamate 421.15, 423.15 (400 MHz, DMSO-d₆) δ 7.55-7.52 (m, 1H),7.38 (d, J = 2.5 Hz, 1H), 7.26 (s, 1H), 7.15 (dd, J = 8.4, 2.1 Hz, 1H),6.81 (d, J = 8.5 Hz, 1H), 6.75-6.73 (m, 1H), 4.37-4.17 (m, 1H),4.01-3.97 (m, 2H), 3.89-3.74 (m, 2H), 2.66-2.60 (m, 3H), 2.16-1.98 (m,2H), 1.89-1.67 (m, 2H), 1.64-1.46 (m, 1H), 1.36-1.29 (m, 1H), 1.26-1.03(m, 1H), 0.90-0.80 (m, 1H) A26

tert-butyl N- [(2S)-1-(3- bromo-5- chlorophenoxy)- 4- carbamoylbutan-2-yl]carbamate 421.05, 423.05 (400 MHz, DMSO-d₆) δ 7.86 (s, 1H),7.29-7.23 (m, 2H), 7.15 (t, J = 2.0 Hz, 1H), 7.07 (t, J = 2.0 Hz, 1H),6.84 (d, J = 8.5 Hz, 1H), 4 .39 (t, J = 8.6 Hz, 1H), 3.88-3.78 (m, 1H),3.75-3.65 (m, 1H), 2.19-2.07 (m, 2H), 1.69-1.52 (m, 2H), 1.38 (s, 9H)A27

tert-butyl N- [(2S)-1-(3- bromo-2- methylphenoxy)- 4- carbamoylbutan-2-yl]carbamate 400.90, 402.95 (400 MHz, DMSO-d₆) δ 7.26 (s, 1H), 7.16(dd, J = 8.1, 1.1 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 7.02-6.91 (m, 1H),6.84 (d, J = 8.4 Hz, 1H), 6.77-6.67 (m, 1H), 3.95-3.92 (m, 1H),3.89-3.73 (m, 2H), 2.24 (s, 3H), 2.19-2.06 (m, 2H), 1.85- 1.77 (m, 1H),1.71-1.51 (m, 1H), 1.39 (s, 9H) A28

tert-butyl N- [(2S)-1-(4- bromo-2- fluorophenoxy)- 4- carbamoylbutan-2-yl]carbamate 405.05, 407.05 (400 MHz, DMSO-d₆) δ 7.75-7.53 (m, 2H),7.40 (d, J = 7.7, 2.3 Hz, 1H), 7.27 (s, 1H), 7.24-7.08 (m, 1H), 6.73 (s,1H), 4.39 (d, J = 8.5 Hz,1H), 4.09-3.91 (m, 4H), 3.88-3.66 (m, 2H),2.66-2.51 (m, 1H), 2.21-2.04 (m, 2H), 1.88-1.66 (m, 2H), 1.64-1.60 (m,1H), 1.33 (s, 1H), 1.29-1.14 (m, 2H) A29

tert-butyl N- [(2S)-1-(3- bromo-4- methylphenoxy)- 4- carbamoylbutan-2-yl]carbamate 401.30, 403.30 (400 MHz, DMSO-d₆) δ 7.27-7.24 (m, 1H),7.15 (d, J = 2.6 Hz, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 6.75 (d, J = 13.5Hz, 2H), 3.86-3.84 (m, 2H), 3.70-3.68 (m, 1H), 2.27 (s, 3H), 2.11-2.09(m, 2H), 1.79-1.77 (m, 1H), 1.60-1.56 (m, 1H), 1.38 (s, 9H) A30

tert-butyl N- [(2S)-1-(3- bromo-5- methylphenoxy)- 4- carbamoylbutan-2-yl]carbamate 401.00, 403.00 (400 MHz, DMSO-d₆) δ 7.26 (s, 1H), 6.97(d, J = 1.4, 1.0 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.83 (d, J = 8.5 Hz,1H), 6.78 (s, 1H), 6.74 (s, 1H), 3.89-3.85 (m, 2H), 3.71-3.67 (m, 1H),2.26 (s, 3H), 2.13-2.09 (m, 2H), 1.87-1.71 (m, 1H), 1.66-1.50 (m, 1H),1.39 (s, 9H) A31

tert-butyl N- [(2S)-1-(5- bromo-2- methylphenoxy)- 4- carbamoylbutan-2-yl]carbamate 401.05, 403.05 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H), 7.09(d, J = 7.4, 1.4 Hz, 2H), 7.02 (d, J = 7.9, 1.8 Hz, 1H), 6.82 (d, J =8.5 Hz, 1H), 6.73 (s, 1H), 3.96-3.92 (m, 1H), 3.84-3.80 (m, 2H),2.20-2.06 (m, 5H), 1.82-1.78 (m, 1H), 1.69-1.57 (m, 1H), 1.39 (s, 9H)A32

tert-butyl N- [(2S)-1-(3- bromo-4- fluorophenoxy)- 4- carbamoylbutan2-yl]carbamate 404.95, 406.95 (400 MHz, DMSO-d₆) δ 7.34-7.23 (m, 3H),7.00-6.96 (m, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 3.90-3.86 (m,2H), 3.71-3.67 (m, 1H), 2.20-2.03 (m, 2H), 1.85-1.72 (m, 1H), 1.64-1.56(m, 1H), 1.39 (s, 9H) A33

tert-butyl N- [(2S)-1-(3- bromo-5- fluorophenoxy)- 4- carbamoylbutan-2-yl]carbamate 405.00, 407.00 (400 MHz, DMSO-d₆) δ 7.26 (s, 1H), 7.09(dt, J = 8.3, 2.0 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.93-6.81 (m, 2H),6.73 (s, 1H), 4.03-3.90 (m, 2H), 3.73-3.69 (m, 1H), 2.17-2.13 (m, 1H),2.14-2.03 (m, 1H), 1.87-1.74 (m, 1H), 1.62-1.58 (m, 1H), 1.38 (s, 9H)A34

tert-butyl N- [(2S)-1-(3- bromo-2- chlorophenoxy)- 4- carbamoylbutan-2-yl]carbamate 421.00, 423.00 (300 MHz, DMSO-d₆) δ 7.66-7.57 (m, 1H),7.32 (dd, J = 7.8, 1.7 Hz, 1H), 7.23 (dd, J = 10.4, 5.6 Hz, 2H), 6.80(d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 4.06-3.89 (m, 2H), 3.78-3.74 (m, 1H),2.24-2.10 (m, 1H), 2.15-2.01 (m, 1H), 1.91-1.73 (m, 1H), 1.63-1.59 (m,1H), 1.37 (s, 9H) A35

tert-butyl N- [(2S)-1-(3- bromo-5-chloro- 2- fluorophenoxy)- 4-carbamoylbutan- 2-yl]carbamate 438.95, 440.95 (400 MHz, DMSO-d₆) 67.42-7.36 (m, 2H), 7.30-7.25 (m, 1H), 6.86 (t, J = 8.7 Hz, 1H), 6.75 (s,1H), 3.76-3.73 (m, 1H), 2.13 (m, 2H), 1.76 (m, 1H), 1.68- 1.60 (m, 3H),1.37 (s, 9H) A36

tert-butyl N- bromo-2-fluoro- 4- methylphenoxy)- 4- carbamoylbutan-2-yl]carbamate 419.05, 421.05 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H),7.17-7.08 (m, 2H), 6.84 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 4.02-3.89 (m,2H), 3.72 (d, J = 4.7 Hz, 1H), 2.31 (s, 3H), 2.21-2.03 (m, 2H),1.86-1.73 (m, 1H), 1.66-1.53 (m, 1H), 1.38 (s, 9H) A37

tert-butyl N- [(2S)-1-(3- bromo-2,4- difluorophenoxy)- 4-carbamoylbutan- 2-yl]carbamate 423.00, 425.00 (400 MHz, DMSO-d₆) δ7.33-7.16 (m, 3H), 6.84 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 4.23 (t, J =6.5 Hz, 1H), 4.06-3.91 (m, 2H), 2.13-2.09 (m, 2H), 1.84-1.74 (m, 1H),1.71-1.61 (m, 1H), 1.38 (s, 9H) A38

methyl 2-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]acetate [(M − 1)]⁻ = 379.20 N/A A39

methyl 3-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]propanoate 395.11 (400 MHz, DMSO-d₆) δ 7.56 (s, 1H), 7.42-7.10(m, 1H), 6.78 (ddt, J = 23.2, 14.9, 8.0 Hz, 4H), 5.86-5.72 (m, 1H),4.13-3.68 (m, 3H), 3.67-3.51 (m, 2H), 3.35-3.32 (m, 1H), 2.72-2.55 (m,3H), 2.26-1.76 (m, 4H), 1.60-1.55(m, 1H), 1.39 (s, 9H) A40

tert-butyl N- [(2S)-1-(3- bromo-2-fluoro- 5- methylphenoxy)- 4-carbamoylbutan- 2-yl]carbamate 419.10, 421.10 (400 MHz, DMSO-d₆) δ 7.27(s, 1H), 7.04 (d, J = 6.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.75 (s,1H), 4.01-3.90 (m, 2H), 3.78-3.69 (m, 1H), 2.27 (s, 3H), 2.22-2.06 (m,2H), 1.87-1.72 (m, 2H), 1.38 (s, 9H) A41

tert-butyl N- [(2S)-1-(3- bromo-2,5- difluorophenoxy)- 4-carbamoylbutan- 2-yl]carbamate 423.05, 425.05 (400 MHz, CDCl₃) δ6.96-6.90 (m, 1H), 6.75-6.68 (m, 1H), 6.19 (s, 1H), 5.52 (s, 1H), 5.10(d, J = 8.1 Hz, 1H), 4.10-3.98 (m, 3H), 2.40 (t, J = 7.0 Hz, 2H),2.11-1.99 (m, 2H), 1.49 (s, 9H) A53

tert-butyl N- [(2S)-1-(3- bromo-2-chloro- 5- fluorophenoxy)- 4-carbamoylbutan- 2-yl]carbamate 439.00, 441.00 (300 MHz, DMSO-d₆) δ 7.34(dd, J = 7.6, 2.7 Hz, 1H), 7.29-7.23 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H),6.76 (s, 1H), 4.12-3.94 (m, 2H), 3.80-3.78 (m, 1H), 2.17-2.13 (m, 2H),1.84-1.80 (m, 1H), 1.64-1.60 (m, 1H), 1.40 (s, 9H)

Tert-butylN-[(1S)-1-[(3-bromophenyl)carbamoyl]-3-carbamoylpropyl]carbamate(Intermediate A42)

Tert-butylN-[(1S)-1-[(3-bromophenyl)carbamoyl]-3-carbamoylpropyl]carbamate. To astirred solution of(2S)-2-[(tert-butoxycarbonyl)amino]-4-carbamoylbutanoic acid (900 mg,3.66 mmol) and 3-bromoaniline (629 mg, 3.66 mmol) in THF (20 mL) wereadded DMAP (45 mg, 0.37 mmol) and DCC (1.13 g, 5.49 mmol) in portions at0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2h at ambient temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by reverse phase flash chromatography with the followingconditions: Spherical C18 Column, 20-40 um, 330 g; Mobile Phase A: Water(plus 10 mmol/L FA), Mobile Phase B: ACN; Gradient: 15% to 44% B in 30min; Detector: UV 254/220 nm. Desired fractions were collected at 40% B,concentrated under reduced pressure and lyophilized to afford titlecompound (700 mg, 43%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ10.16 (s, 1H), 7.98 (t, J=1.9 Hz, 1H), 7.51 (dt, J=7.8, 1.8 Hz, 1H),7.32-7.21 (m, 4H), 6.80-6.77 (m, 1H), 4.02 (td, J=8.3, 7.6, 4.9 Hz, 1H),2.15-2.11 (m, 2H), 1.97-1.72 (m, 2H), 1.39 (s, 9H); LC/MS (ESI, m/z):[(M+1)]⁺=400.10, 402.10

The intermediates in Table 11 were prepared according to the procedureto prepare Intermediate A42.

TABLE 11 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A43

tert-butyl N-R15)-1- [(3-bromo-2- chlorophenyl) carbamoyl]-3-carbamoylpropyl] carbamate 433.95, 435.95 (400 MHz, DMSO-d₆) δ 7.84 (d,J = 8.1 Hz, 1H), 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.36-7.21 (m, 4H), 6.82(s, 1H), 4.16-4.12 (m, 1H), 2.25-2.13 (m, 2H), 2.02-1.95 (m, 1H), 1.86-1.78 (m, 1H), 1.41 (s, 9H) A44

tert-butyl N-[(1S)-1- [(3-bromo-2- fluorophenyl) carbamoyl]-3-carbamoylpropyl] carbamate 418.05, 420.05 (300 MHz, DMSO-d₆) δ 9.87 (s,1H), 7.87 (t, J = 7.7 Hz, 1H), 7.48-7.43 (m, 1H), 7.33 (s, 1H),7.24-7.04 (m, 2H), 6.82 (s, 1H), 4.19 (q, J = 7.4 Hz, 1H), 2.34-2.08 (m,2H), 1.98-1.68 (m, 2H), 1.40 (s, 9H) A45

tert-butyl N-[(1S)-1- [(3- bromophenyl) carbamoyl]-3- carbamoylpropyl]carbamate [(M − 1)]⁻ = 432.00, 434.00 N/A A46

Tert-butyl N-[(1S)-1- [(3-bromo-5- methylphenyl) carbamoyl]-3-carbamoylpropyl] carbamate 414.15, 416.15 (300 MHz, DMSO-d₆) δ 10.06 (s,1H), 7.76 (s, 1H), 7.36-7.28 (m 2H), 7.14-7.06 (m, 2H), 6.79 (s, 1H),4.01 (q, J = 7.4 Hz, 1H), 2.29 (s, 3H), 2.15 (q, J = 7.8 Hz, 2H),1.95-1.73 (m, 2H), 1.40 (s, 9H) A47

tert-butyl N-[(1S)-1- [(3-bromo-2- methylphenyl) carbamoyl]-3-carbamoylpropyl] carbamate 414.10, 416.10 (300 MHz, DMSO-d₆) δ 9.59 (s,1H), 7.47 (dd, J = 8.0, 1.3 Hz, 1H), 7.39- 7.27 (m, 2H), 7.21-7.01 (m,2H), 6.81 (s, 1H), 4.06 (t, J = 7.2 Hz, 1H), 2.26 (s, 3H), 2.25-2.09 (m,2H), 2.08-1.71 (m, 2H), 1.41 (s, 9H) A48

tert-butyl N-[(1S)-1- [(3-bromo-5- fluorophenyl) carbamoyl]-3-carbamoylpropyl] carbamate 418.10, 420.10 (300 MHz, DMSO-d₆) δ 10.33 (s,1H), 7.71 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 11.2 Hz, 1H), 7.39- 7.06 (m,3H), 6.80 (s, 1H), 4.01 (s, 1H), 2.17 (q, J = 7.6 Hz, 2H), 1.90- 1.74(m, 2H), 1.40 (s, 9H)

Tert-butyl(S)-(5-amino-1-((3-bromo-2-fluorophenyl)amino)-5-oxopentan-2-yl)carbamate(Intermediate A49)

Step 1: methyl(4S)-5-[(3-bromo-2-fluorophenyl)amino]-4-[(tert-butoxycarbonyl)amino]pentanoate.To a stirred solution of methyl(4S)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoate (3.01 g, 12.25 mmol)and 3-bromo-2-fluoroaniline (1.94 g, 10.2 mmol) in CH₂Cl₂ (40 mL) wereadded NaBH(OAc)₃ (4.33 g, 20.4 mmol) and HOAc (0.67 g, 11.2 mmol) inportions at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 16 h at room temperature under nitrogenatmosphere followed by concentration under reduced pressure. The residuewas purified by reverse phase flash chromatography with the followingconditions: Spherical C18 Column, 20-40 um, 330 g; Mobile Phase A: Water(plus 10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Gradient: 30% to 50% B in10 min; Detector: UV 254/220 nm. Desired fractions were collected at 43%B, concentrated under reduced pressure and lyophilized to afford titlecompound (2.1 g, 49%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.91(t, J=8.0 Hz, 1H), 6.83-6.75 (m, 2H), 6.75 (dd, J=7.8, 1.6 Hz, 1H), 5.75(s, 1H), 3.62 (s, 1H), 3.56 (s, 3H), 3.08 (t, J=6.2 Hz, 2H), 2.42-2.23(m, 2H), 1.61-1.57 (m, 1H), 1.39-1.35 (m, 8H), 1.29-1.25 (m, 2H); LC/MS(ESI, m/z): [(M+1)]⁺=419.15, 421.15.

The intermediates in Table 12 were prepared according to step 1 of theprocedure to prepare Intermediate A49.

TABLE 12 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMRA49-1-1

methyl (4S)-5-[(3- bromo-2- fluorophenyl)(methyl) amino]-4-[(tert-butoxycarbonyl) amino]pentanoate 433.20, 435.20 (400 MHz, DMSO-d₆) δ7.09- 7.06 (m, 1H), 7.01-6.86 (m, 2H), 6.60 (d, J = 9.2 Hz, 1H),3.69-3.67 (m, 1H), 3.57 (s, 3H), 3.19-3.08 (m, 2H), 2.89 (s, 3H), 2.29(dd, J = 8.6, 6.5 Hz, 2H), 1.74 (dtd, J= 16.0, 7.9, 3.8 Hz, 1H), 1.48(ddt, J = 13.9, 9.6, 7.1 Hz, 1H), 1.33 (s, 9H).

Step 2: Tert-butyl(S)-(5-amino-1-((3-bromo-2-fluorophenyl)amino)-5-oxopentan-2-yl)carbamate.To a mixture of methyl(4S)-5-[(3-bromo-2-fluorophenyl)amino]-4-[(tert-butoxycarbonyl)amino]pentanoate(1.02 g, 2.43 mmol) and NH₃ (g) in MeOH (5.00 mL, 7M) in a sealed tubewas was stirred for 16 h at 70° C. After cooling down to ambienttemperature, the resulting mixture was concentrated under reducedpressure to afford Tert-butyl(S)-(5-amino-1-((3-bromo-2-fluorophenyl)amino)-5-oxopentan-2-yl)carbamate(691 mg, 70%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (s,1H), 6.91 (t, J=8.0 Hz, 1H), 6.85-6.72 (m, 3H), 6.73-6.69 (m, 2H), 3.58(s, 1H), 3.08 (s, 2H), 2.19-1.98 (m, 2H), 1.81-1.71 (m, 1H), 1.57-1.53(m, 1H), 1.38 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=404.20, 406.20.

The intermediates in Table 13 were prepared according to step 2 of theprocedure to prepare Intermediate A49.

TABLE 13 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR A50

tert-butyl (S)- (5-amino-1-((3- bromo-2- fluorophenyl) (methyl)amino)-5-oxopentan-2- yl)carbamate 418.20, 420.20 (400 MHz, DMSO-d₆) δ 7.22 (s,1H), 7.06 (ddd, J = 7.8, 5.8, 1.7 Hz, 1H), 7.01- 6.86 (m, 2H), 6.69 (s,1H), 6.57 (d, J = 9.2 Hz, 1H), 3.67-3.64 (m, 1H), 3.22 (m, 3H), 2.86 (s,3H), 2.09-1.96 (m, 2H), 1.70-1.66 (m, 1H), 1.33 (s, 9H)

Tert-butylN-[(3S,4R)-1-Carbamoyl-4-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)pentan-3-yl]carbamate(Intermediate B)

Step 1. 3-[2-(Prop-2-yn-1-yloxy)ethoxy]prop-1-yn. To a solution ofethylene glycol (10.0 g, 161 mmol) in THF (250 mL) was added NaH (16.1g, 402 mmol, 60% dispersed in mineral oil) in portions at 0° C. undernitrogen atmosphere. The resulting mixture was stirred for 30 min at 0°C. under nitrogen atmosphere. To the above mixture was added a solutionof propargyl bromide (47.9 g, 402 mmol) in THF (50.0 mL) at 0° C. over10 min. The resulting mixture was stirred for 16 hours at roomtemperature under nitrogen atmosphere. The resulting mixture wasquenched with saturated aqueous ammonium chloride (200 mL) at 0° C. Theresulting mixture was extracted with ethyl acetate (2×300 mL). Thecombined organic layer was washed with brine (300 mL) and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with 1% ethyl acetate in petroleum ether toafford the title compound as a brown oil (8.20 g, 37%): ¹H NMR (400 MHz,CDCl₃) δ 4.22 (dd, J=2.4, 0.9 Hz, 4H), 3.73 (d, J=1.0 Hz, 4H), 2.44 (td,J=2.4, 0.8 Hz, 2H); MS (ESI, m/z): [(M+18)]⁺=156.20.

The intermediates in Table 14 were prepared according to Step 1 of theprocedure to prepare Intermediate B.

TABLE 14 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name ¹H-NMR B-1-1

3-[3-(Prop-2-yn-1- yloxy)propoxy]prop- 1-yne ¹H NMR (400 MHz, CDCl₃) δ4.10- 4.08 (m, 4H), 3.55 (t, J = 6.3 Hz, 4H), 2.41 (d, J = 4.8 Hz, 2H),1.83 (p, J = 6.3 Hz, 2H). B-1-2

1,4-bis(prop-2-yn-1- yloxy)butane ¹H NMR (400 MHz, CDCl₃) δ 4.17- 4.15(m, 4H), 3.60-3.53 (m, 4H), 2.43 (t, J = 2.4 Hz, 2H), 1.74-1.68 (m, 4H).B-1-3

1,5-bis(prop-2-yn-1- yloxy)pentane ¹H NMR (400 MHz, CDCl₃) δ 4.17- 4.15(m, 4H), 3.55 (t, J = 6.5 Hz, 4H), 2.44 (t, J = 2.4 Hz, 2H), 1.71-1.60(m, 4H), 1.53-1.40 (m, 2H). B-1-4

1,6-bis(prop-2-yn-1- yloxy)hexane ¹H NMR (400 MHz, CDCl₃) δ 4.17- 4.15(m, 4H), 3.54 (td, J = 6.6, 2.7 Hz, 4H), 2.44 (q, J = 2.3 Hz, 2H),1.69-1.59 (m, 4H), 1.41 (h, J = 3.2 Hz, 4H). B-1-5

1,7-bis(prop-2-yn-1- yloxy)heptane ¹H NMR (400 MHz, CDCl₃) δ 4.17- 4.15(m, 4H), 3.53 (t, J = 6.6 Hz, 4H), 2.44 (d, J = 2.5 Hz, 2H), 1.62 (d, J= 13.8 Hz, 4H), 1.44-1.34 (m, 6H). B-1-6

1,8-bis(prop-2-yn-1- yloxy)octane ¹H NMR (400 MHz, CDCl₃) δ 4.17- 4.15(m, 4H), 3.52 (t, J = 6.6 Hz, 4H), 2.43 (t, J = 2.4 Hz, 2H), 1.67-1.53(m, 4H), 1.43-1.28 (m, 8H). B-1-7^(a)

5-(prop-2-yn-1- yloxy)pentan-l-ol ¹H NMR (400 MHz, CDCl₃) δ 4.16 (d, J =2.3 Hz, 2H), 3.68 (td, J = 6.5, 2.0 Hz, 2H), 3.55 (td, J = 6.5, 1.5 Hz,2H), 2.44 (q, J = 2.6 Hz, 1H), 1.70-1.59 (m, 4H), 1.51-1.43 (m, 3H).^(a)Propargyl bromide (1 eq.) and NaH (1.1 eq.) used.

Step 2.3-(3-Methyl-2-oxo-5-[3-[2-(prop-2-yn-1-yloxy)ethoxy]prop-1-yn-1-yl]-1,3-benzodiazol-1-yl)piperidine-2,6-dione.To a solution of3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione(1.00 g, 2.96 mmol), Pd(PPh₃)₄(342 mg, 0.30 mmol) and CuI (56.3 mg, 0.30mmol) in DMSO (20 mL) were added TEA (10 mL) and3-[2-(prop-2-yn-1-yloxy)ethoxy]prop-1-yne (3.27 g, 23.7 mmol). Themixture was purged with nitrogen for three times and stirred for 3 hoursat 80° C. under nitrogen atmosphere. The resulting mixture was cooleddown to room temperature and concentrated under reduced pressure. Theresidue was acidified to pH 5 with acetic acid and purified by reversedphase flash chromatography with the following conditions: Column:WelFlash™ C18-I, 20-40 um, 330 g; Eluent A: water (plus 10 mmol/L AcOH);Eluent B: ACN; Gradient: 20%-40% B in 20 min; Flow rate: 80 mL/min;Detector: UV 220/254 nm; desired fractions were collected at 37% B andconcentrated under reduced pressure. The crude product was re-purifiedby silica gel column chromatography, eluted with 50% ethyl acetate inpetroleum ether to afford the title compound as a light brown solid (450mg, 39%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.38-7.32 (m, 1H),7.21-7.10 (m, 2H), 5.39 (dd, J=12.6, 5.4 Hz, 1H), 4.39 (d, J=2.4 Hz,2H), 4.16 (t, J=2.4 Hz, 2H), 3.68-3.61 (m, 4H), 3.44 (dd, J=3.4, 2.3 Hz,1H), 3.34 (d, J=2.3 Hz, 3H), 2.88 (t, J=15.6 Hz, 1H), 2.76-2.57 (m, 2H),2.08-1.98 (m, 1H); MS (ESI, m/z): [(M+1)]⁺=396.15.

Step 3. tert-Butyl((2R,3S)-6-amino-2-((4-(3-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)prop-1-yn-1-yl)benzyl)oxy)-6-oxohexan-3-yl)carbamate.The title compound was prepare according to Step 2 above: ¹H NMR (400MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.69 (d, J=13.2 Hz, 1H), 7.54-7.27 (m,4H), 7.20 (d, J=12.8 Hz, 1H), 7.14 (t, J=7.9 Hz, 1H), 6.73-6.59 (m, 1H),5.39 (dd, J=12.7, 5.4 Hz, 1H), 4.48 (s, 1H), 4.41 (s, 3H), 4.22 (t,J=6.6 Hz, 1H), 3.70 (s, 2H), 3.41 (d, J=6.0 Hz, 1H), 3.35 (s, 2H), 3.33(s, 3H), 2.94-2.83 (m, 1H), 2.76-2.58 (m, 2H), 2.54 (s, 1H), 2.13-1.97(m, 2H), 1.76 (s, 1H), 1.67-1.60 (m, 1H), 1.37 (s, 9H), 1.26 (d, J=19.3Hz, 1H), 1.06 (d, J=6.1 Hz, 2H), 0.89 (dt, J=13.4, 6.8 Hz, 2H); MS (ESI,m/z): [(M+1)]⁺=728.3.

The intermediates in Table 15 were prepared according to Step 2 and 3 ofthe procedure to prepare Intermediate B.

TABLE 15 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMRB-2-1

3-[3-methyl-2- oxo-4-[3-(prop-2- yn-1-yloxy)prop- 1-yn-1-yl]-1,3-benzodiazol-1- yl]piperidine-2,6- dione 352.1 (400 MHz, CD₃OD) δ 7.19(d, J = 1.2 Hz, 1H) 7.13 (d, J = 1.3 Hz, 1H), 7.06 (s, 1H), 5.37 (t, J =4.1 Hz, 1H), 4.56 (s, 2H), 3.76 (d, J = 1.7 Hz, 3H), 2.96-2.93 (m, 2H),2.82-2.76 (m, 2H), 2.18-2.13 (m, 1H) B-2-2

3-[3-methyl-2- oxo-4-[3-[2- (prop-2-yn-1- yloxy)ethyoxy]prop-1-yn-1-yl]-1,3- benzodiazol-1- yl]piperidine-2,6- dione 396.2 (400 MHz,CD₃OD) δ 7.24-7.08 (m, 3H), 5.38 (s, 1H), 4.51 (s, 2H), 4.26-4.20 (m,2H), 3.81- 3.78 (m, 3H), 3.53 (s, 2H), 3.20 (s, 2H), 2.86 (s, 4H), 2.21(s, 1H). B-2-3

1-methyl-3-(3- methyl-2-oxo-5- [3-[2-(prop-2-yn- 1- yloxy)ethyoxy]prop-1-yn-1-yl]-1,3- benzodiazol-1- yl]piperidine-2,6- dione 410.3 (400 MHz,DMSO-d₆) δ 7.39 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.01 (q,J = 7.6 Hz, 1H), 5.51-5.39 (m, 1H), 4.48 (d, J = 7.2 Hz, 3H), 3.71 (s,4H), 3.64 (d, J = 6.8 Hz, 3H), 3.03 (d, J = 6.3 Hz, 3H), 2.83-2.66 (m,2H), 2.03 (s, 4H). B-2-4

3-[3-methyl-2- oxo-5-[3-[2- (prop-2-yn-1- yloxy)propoxy]prop-1-yn-1-yl]- 2,3-dihydro-1H- 1,3-benzodiazol- 1-yl]piperidine- 2,6-dione408.2 (400 MHz, CDCl₃) δ 8.36 (s, 1H), 7.22 (dd, J = 8.2, 1.5 Hz, 1H),7.14 (d, J = 1.5 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.22 (dd, J = 12.7,5.3 Hz, 1H), 3.70- 3.66 (m, 4H), 3.44 (s, 3H), 3.04- 2.61 (m, 4H), 2.44(t, J = 2.4 Hz, 1H), 1.51-1.27 (m, 6H). B-2-5

3-[3-methyl-2- oxo-4-[3-[2- (prop-2-yn-1- yloxy)propoxy]prop-1-yn-1-yl]- 1,3-benzodiazol- 1-yl]piperidine- 2,6-dione 410.2 (400 MHz,DMSO-d₆) δ 11.11 (d, J = 8.1 Hz, 1H), 7.21-7.08 (m, 2H), 7.04 (t, J =7.9 Hz, 1H), 5.41 (dd, J = 12.5, 5.4 Hz, 1H), 4.43 (d, J = 10.2 Hz, 2H),4.17- 4.05 (m, 2H), 3.73-3.55 (m, 5H), 3.55-3.47 (m, 2H), 3.40 (d, J =4.8 Hz, 1H), 2.98-2.82 (m, 1H), 2.77-2.56 (m, 2H), 2.04 (d, J = 12.4 Hz,1H), 1.87-1.72 (m, 2H). B-2-6

3-[3-methyl-2- oxo-5-[3-[2- (prop-2-yn-1- yloxy)butoxy]prop-1-yn-1-yl]-1,3- benzodiazol-1- yl]piperidine-2,6- dione 422.2 (400 MHz,DMSO-d₆) δ 11.12 (s, 1H), 7.34 (d, J = 1.3 Hz, 1H), 7.20-7.10 (m, 2H),5.40 (dd, J = 12.7, 5.3 Hz, 1H), 4.36 (s, 2H), 4.11 (d, J = 2.4 Hz, 2H),3.56-3.50 (m, 2H), 3.46 (q, J = 4.6, 3.2 Hz, 2H), 3.40 (d, J = 4.9 Hz,1H), 2.97-2.83 (m, 1H), 2.78-2.58 (m, 2H), 2.03 (ddd, J = 16.2, 7.4, 4.6Hz, 1H), 1.60-1.58 (m, 5H), 1.24 (s, 1H), 1.21-1.06 (m, 1H). B-2-7

3-[3-methyl-2- oxo-4-[3-[4- (prop-2-yn-1- yloxy)butoxy]prop-1-yn-1-yl]-1,3- benzo diazol-1- yl]piperidine-2,6- dione 424.2 (400 MHz,DMSO-d₆) δ 11.12 (s, 1H), 7.16 (dd, J = 19.4, 7.8 Hz, 2H), 7.04 (t, J =7.8 Hz, 1H), 5.41 (dd, J = 12.7, 5.4 Hz, 1H), 4.43 (s, 2H), 4.10 (d, J =2.4 Hz, 2H), 3.65 (s, 3H), 3.55 (d, J = 11.7 Hz, 2H), 3.46 (d, J = 11.6Hz, 2H), 3.38 (t, J = 2.4 Hz, 1H), 2.94-2.86 (m, 1H), 2.73-2.58 (m, 2H),2.03 (dd, J = 11.6, 5.9 Hz, 1H), 1.60 (m, 4H). B-2-8

3-[3-methyl-2- oxo-5-(3-[[5- (prop-2-yn-1- yloxy)pentyl]oxy]prop-1-yn-1-yl)- 1,3-benzodiazol- 1-yl]piperidine- 2,6-dione 436.3 (400MHz, CDCl₃) δ 8.12 (s, 1H), 7.22 (dd, J = 8.1, 1.5 Hz, 1H), 7.14 (d, J =1.6 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.21 (dd, J = 12.6, 5.3 Hz, 1H),4.38 (s, 2H), 4.15 (d, J = 2.4 Hz, 2H), 3.61 (t, J = 6.6 Hz, 2H), 3.55(t, J = 6.5 Hz, 2H), 3.45 (s, 3H), 3.03-2.93 (m, 1H), 2.79 (dqd, J =39.2, 13.3, 4.9 Hz, 2H), 2.43 (t, J = 2.4 Hz, 1H), 2.32-2.21 (m, 1H),1.75-1.61 (m, 4H), 1.56- 1.43 (m, 2H). B-2-9

3-[3-methyl-2- oxo-4-(3-[[5- (prop-2-yn-1- yloxy)pentyl]oxy]prop-1-yn-1-yl)- 1,3-benzodiazol- 1-yl]piperidine- 2,6-dione 438.3 (400MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.18 (dd, J = 7.9, 1.2 Hz, 1H), 7.13 (dd,J = 7.9, 1.1 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 5.40 (dd, J = 12.6, 5.3Hz, 1H), 4.43 (s, 2H), 4.10 (d, J = 2.4 Hz, 2H), 3.54 (t, J = 6.4 Hz,2H), 3.43 (t, J = 6.4 Hz, 2H), 3.38 (t, J = 2.4 Hz, 1H), 3.31 (s, 2H),2.95-2.83 (m, 1H), 2.75 (dd, J = 12.8, 4.3 Hz, 1H), 2.73-2.64 (m, 1H),2.09-1.99 (m, 1H), 2.02 (s, 1H), 1.71-1.48 (m, 4H), 1.43- 1.31 (m, 2H).B-2-10

3-[3-methyl-2- oxo-5-(3-[[6- (prop-2-yn-1- yloxy)hexyl]oxy]prop-1-yn-1-yl)- 2,3-dihydro-1H- 1,3-benzodiazol- 1-yl]piperidine-2,6-dione 452.2 (400 MHz, DMSO-d₆) δ 11.12 (d, J = 4.2 Hz, 1H), 7.33 (d,J = 5.9 Hz, 1H), 7.19-7.11 (m, 2H), 5.39 (dt, J = 10.3, 5.0 Hz, 1H),4.35 (d, J = 5.6 Hz, 2H), 4.08 (dd, J = 5.6, 2.4 Hz, 2H), 3.50 (q, J =6.2 Hz, 2H), 3.45-3.37 (m, 3H), 2.89 (dd, J = 17.0, 12.9 Hz, 1H),2.78-2.58 (m, 2H), 2.02 (dt, J = 15.8, 6.0 Hz, 2H), 1.53- 1.50 (m, 4H),1.42-1.21 (m, 5H), 1.20-1.14 (m, 1H). B-2-11

3-[3-methyl-2- oxo-4-(3-[[6- (prop-2-yn-1- yloxy)hexyl]oxy]prop-1-yn-1-yl)- 1,3-benzodiazol- 1-yl]piperidine- 2,6-dione 452.2 (400MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.13 (d, J =7.8 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 5.41 (dd, J = 12.6, 5.4 Hz, 1H),4.42 (s, 2H), 4.09 (d, J = 2.4 Hz, 2H), 3.65 (s, 3H), 3.53 (t, J = 6.5Hz, 2H), 3.45-3.34 (m, 3H), 2.90 (ddd, J = 17.1m 12.8, 5.1 Hz, 1H),2.78- 2.59 (m, 2H), 2.10-1.95 (m, 1H), 1.53 (dp, J = 19.6, 7.1, 6.4 Hz,4H), 1.35-1.32 (m, 4H). B-2-12

1-methyl-3-[3- methyl-2-oxo-5- (3-[[6-(prop-2- yn-1- yloxy)hexyl]oxy]prop-1-yn-1-yl)- 1,3-benzodiazol- 1-yl]piperidine- 2,6-dione N/A (400MHz, DMSO-d₆) δ 7.34 (s, 1H), 7.15 (d, J = 1.0 Hz, 2H), 5.76 (s, 1H),5.46 (dd, J = 13.0, 5.3 Hz, 1H), 4.36 (s, 2H), 4.11- 3.99 (m, 2H), 3.51(t, J = 6.5 Hz, 2H), 3.46-3.36 (m, 3H), 3.32 (s, 1H), 3.04 (s, 3H),3.03-2.91 (m, 1H), 2.83-2.75 (m, 1H), 2.70 (td, J = 13.1, 4.5 Hz, 1H),2.09-1.97 (m, 1H), 1.55-1.52 (m, 4H), 1.43-1.30 (m, 5H). B-2-13

3-[3-methyl-2- oxo-5-(3-[[7- (prop-2-yn-1- yloxy)heptyl]oxy]prop-1-yn-1-yl)- 1,3-benzodiazol- 1-yl]piperidine- 2,6-dione 488.2 (400MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.33 (d, J = 1.4 Hz, 1H), 7.19-7.10 (m,2H), 5.39 (dd, J = 12.7, 5.3 Hz, 1H), 4.35 (s, 2H), 4.09 (d, J = 2.3 Hz,2H), 3.51 (t, J = 6.5 Hz, 2H), 3.44-3.37 (m, 3H), 3.32 (s, 1H),2.96-2.84 (m, 1H), 2.77-2.59 (m, 2H), 2.09- 1.97 (m, 1H), 1.54-1.51 (m,4H), 1.31 (s, 7H). B-2-14

3-[3-methyl-2- oxo-5-(3-[[8- (prop-2-yn-1- yloxy) oxtyl]oxy]prop-1-yn-1-yl)-1,3- benzodiazol-1- yl]piperidine-2,6- dione 502.3 (400 MHz,CDCl₃) δ 8.16 (s, 1H), 7.22 (dd, J = 8.1, 1.5 Hz, 1H), 7.14 (d, J = 1.5Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.22 (dd, J = 12.7, 5.3 Hz, 1H), 4.38(s, 2H), 4.15 (d, J = 2.4 Hz, 2H), 3.59 (t, J = 6.7 Hz, 2H), 3.52 (t, J= 6.6 Hz, 2H), 3.44 (s, 3H), 3.03-2.67 (m, 3H), 2.44 (t, J = 2.4 Hz,1H),1.78-1.55 (m, 6H), 1.47-1.26 (m, 7H). B-2-15

3-[3-methyl-2- oxo-5-(3-[2-[2- (prop-2-yn-1- yloxy)ethoxy]ethoxy]prop-1-yn- 1-yl)-2,3- dihydro-1H-1,3- benzodiazol-1-yl]piperidine-2,6- dione 462.3 (400 MHz, DMSO-d₆) δ 11.12 (d, J = 6.8Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.19-7.09 (m, 2H), 5.39 (dt, J =12.7, 6.8 Hz, 1H), 4.43-4.36 (m, 2H), 4.17-4.11 (m, 2H), 3.66-3.60 (m,2H), 3.59- 3.49 (m, 6H), 3.45-3.40 (m, 1H), 3.35 (s, 1H), 3.32 (d, J =0.9 Hz, 1H), 2.95-2.81 (m, 1H), 2.75- 2.55 (m, 2H), 2.08-1.95 (m, 1H),1.31-1.12 (m, 1H). B-2-16

3-[3-methyl-2- oxo-4-(3-[2-[2- (prop-2-yn-1- yloxy)ethoxy]ethoxy]prop-1-yn-1- yl)-1,3- benzodiazol-1- yl]piperidine-2,6- dione440.2 (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.19 (dd, J = 8.0, 1.0 Hz, 1H),7.00 (d, J = 7.9 Hz, 1H), 6.78 (dd, J = 7.9 Hz, 1.1 Hz, 1H), 5.22 (dd, J= 12.5, 5.3 Hz, 1H), 4.49 (s, 2H), 4.23 (d, J = 2.4 Hz, 2H), 3.84-3.78(m, 1H), 3.80 (s, 3H), 3.81-3.69 (m, 6H), 3.01- 2.92 (m, 1H), 2.91-2.67(m, 2H), 2.45 (t, J = 2.4 Hz, 1H), 2.30- 2.19 (m, 1H), 1.02-0.87 (m,1H). B-2-17

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (4,7,10,13- tetraxahexadeca-1,15-diyn-1- yl)phenyl]methoxy] pentan-3- yl]carbamate 561.3 (400 MHz,CDCl₃) δ 7.46-7.40 (m, 2H), 7.29 (s, 2H), 6.47 (s, 1H), 5.44 (s, 1H),4.45 (s, 2H), 4.22 (d, J = 2.4 Hz, 3H), 3.82- 3.77 (m, 2H), 3.75-3.70(m, 10H), 3.62 (dd, J = 6.4, 3.6 Hz, 1H), 2.45 (t, J = 2.4 Hz, 1H),2.33-2.26 (m, 2H), 2.02-1.96 (m, 1H), 1.73 (ddt, J = 18.9, 12.0, 6.4 Hz,2H), 1.45 (s, 9H), 1.21 (d, J = 6.3 Hz, 3H). B-2-18

tert-butyl 3-[2-[2- (trimethylsilyl) ethynyl]phenyl] propanoate N/A (400MHz, DMSO-d₆) δ 7.41 (dd, J = 7.4, 1.3 Hz, 1H), 7.35-7.28 (m, 2H),7.23-7.21 (m, 1H), 2.99- 2.92 (m, 2H), 2.55-2.53 (m, 2H), 1.38 (s, 9H),0.24 (s, 9H). B-3-1

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (3-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo,1,3- benzodiazol-4-yl]methoxy]prop-1- yn-1- yl)phenyl]methoxy] pentan-3- yl]carbamate 662.4(400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.18 (d, J = 7.9, Hz, 2H), 7.35 (d,J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.10-6.98 (m,1H), 6.68 (s, 1H), 6.63 (d, J = 9.0 Hz, 1H), 5.76 (s, 1H), 5.40 (dd, J =12.5, 5.3 Hz, 1H), 4.85 (s, 2H), 4.56-4.45 (m, 3H), 4.33 (d, J = 4.2 Hz,1H), 3.31 (s, 4H), 2.95-2.83 (m, 1H), 2.75-2.58 (m, 2H), 2.01 (s, 3H),1.78 (s, 1H), 1.47 (s, 1H), 1.38 (s, 7H), 1.07 (d, J = 6.0 Hz, 2H), 1.04(d, J = 6.1 Hz, 3H). B-3-2

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-([3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo,1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)prop-1- yn-1- yl]phenyl]methoxy) pentan-3-yl]carbamate 686.5 (400 MHz, DMSO-d₆) δ 11.12 (d, J = 6.2 Hz, 1H), 7.42(t, J = 7.9 Hz, 2H), 7.38-7.25 (m, 2H), 7.17 (dt, J = 15.2, 8.2 Hz, 3H),7.03 (q, J = 7.9 Hz, 1H), 6.64 (dd, J = 19.5, 10.8 Hz, 2H), 5.40 (dt, J= 12.3, 5.8 Hz, 1H), 4.59 (d, J = 7.3 Hz, 2H), 4.57-4.43 (m, 4H),4.27-4.17 (m, 1H), 3.66-3.63 (m, 3H), 3.43 (dq, J = 18.0, 6.0 Hz, 1H),2.76-2.59 (m, 1H), 2.49 (s, 1H), 2.07-1.99 (m, 3H), 1.38-1.36 (m, 9H),1.11- 1.00 (m, 6H). B-3-3

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[2-([3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo,1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)ethoxy] prop-1-yn-1- yl]phenyl)methoxy] pentan-3-yl]carbamate 730.4 (400 MHz, CD₃OD) δ 7.75-7.62 (m, 1H), 7.53-7.30 (m,3H), 7.28-6.92 (m, 3H), 5.51 (s, 1H), 5.36 (s, 1H), 4.69-4.23 (m, 6H),3.84-3.77 (m, 6H), 6.58-3.51 (m, 2H), 3.04-2.68 (m, 3H), 2.20 (s, 3H),1.98 (s, 1H), 1.51-1.41 (m, 7H), 1.32 (s, 2H), 1.18 (d, J = 6.6 Hz, 2H),1.00-0.92 (m, 2H). B-3-4

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[2-([3-[3- methyl-1-(1-methyl-2,6- dioxopiperidin-3- yl)-3-oxo,1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)ethoxy] prop-1-yn-1- yl]phenyl)methoxy] pentan-3-yl]carbamate 744.5 (400 MHz, DMSO-d₆) δ 7.51- 7.49 (m, 1H), 7.39 (d, J =7.5 Hz, 2H), 7.35-7.34 (m, 3H), 7.24-7.07 (m, 3H), 7.01 (q, J = 7.6 Hz,1H), 6.71-6.56 (m, 2H), 5.76-5.74 (m, 1H), 5.50-5.41 (m, 1H), 4.47-4.41(m, 7H), 3.78- 3.56 (m, 7H), 3.46-3.38 (m, 2H), 3.12-2.87 (m, 4H),2.83-2.66 (m, 2H), 2.03 (s, 4H), 1.76 (s, 1H), 1.46 (s, 2H), 1.23 (d, J= 9.3 Hz, 1H), 1.08-1.06 (m, 4H). B-3-5

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[3-([3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro- 1H-1,3-benzodiazol-5- yl]prop-2-yn-1- yl]oxy)propoxy] prop-1-yn-1-yl]phenyl)methoxy] pentan-3- yl]carbamate 744.3 (400 MHz, CDCl₃) δ 9.30(s, 1H), 7.40 (dd, J = 8.1, 3.1 Hz, 2H), 7.25-7.22 (m, J 3H), 7.12 (s,1H), 6.76 (d, J = 8.0 Hz, 1H), 5.22 (dd, J = 12.9, 5.2 Hz, 1H), 4.92 (d,J = 9.8 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.38 (s, 4H), 3.74 (d, J =2.2 Hz, 1H), 3.59 (s, 1H), 3.40 (d, J = 2.6 Hz, 3H), 2.98-2.78 (m, 3H),2.37-2.17 (m, 5H), 1.99-1.96 (m, 3H), 1.44 (s, 9H), 1.19 (dd, J = 6.4,1.6 Hz, 3H), 0.93-0.88 (m, 3H). B-3-6

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[3-([3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)propoxy] prop-1-yn-1- yl]phenyl)methoxy]pentan-3- yl]carbamate 744.5 (400 MHz, CD₃OD) δ 7.71-6.80 (m, 7H), 5.35(s, 1H), 4.64-4.17 (m, 6H), 3.75 (s, 6H), 3.51 (s, 3H), 2.88-2.84 (m,3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.40-1.36 (m, 9H), 1.18 (s, 4H). B-3-7

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[4-([3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]prop-2-yn-1- yl]oxy)butoxy] prop-1-yn-1- yl]phenyl)methoxy] pentan-3-yl]carbamate 758.5 (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.40 (d, J = 8.1Hz, 2H), 7.34-7.32 (m, 3H), 7.23-7.11 (m, 3H), 6.72-6.59 (m, 2H), 5.76(s, 1H), 5.39 (dd, J = 12.8, 5.3 Hz, 1H), 4.56-4.44 (m, 2H), 4.37- 4.35(m, 4H), 3.56-3.53 (m, 4H), 3.42 (q, J = 5.6 Hz, 1H), 3.34 (s, 3H),2.92-2.84 (m, 1H), 2.77- 2.59 (m, 2H), 2.15-1.96 (m, 3H), 1.78 (dt, J =6.9, 3.8 Hz, 1H), 1.64-1.61 (m, 4H), 1.48 (dt, J = 9.2, 4.9 Hz, 1H),1.38 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H). B-3-8

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[4-([3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)butoxy] prop-1-yn-1- yl]phenyl)methoxy] pentan-3-yl]carbamate 758.5 (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.40 (d, J = 7.9Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.26- 7.15 (m, 2H), 7.12 (d, J = 7.8Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.74-6.56 (m, 2H), 5.40 (dd, J =12.6, 5.4 Hz, 1H), 4.55-4.38 (m, 4H), 4.36 (s, 2H), 3.60-3.50 (m, 4H),3.43 (dq, J = 17.5 5.9 Hz, 2H), 2.95-2.83 (m, 2H), 2.78- 2.58 (m, 2H),2.15-1.96 (m, 3H), 1.76 (q, J = 9.9, 9.0 Hz, 1H), 1.68-1.55 (m, 5H),1.55- 1.42 (m, 1H), 1.38 (s, 10H), 1.07 (d, J = 6.0 Hz, 3H). B-3-9

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[[5-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]prop-2-yn-1- yl]oxy)pentyl] oxy]prop-1-yn-1- yl)phenyl]methoxy]pentan-3- yl]carbamate 772.4 (400 MHz, CD₃OD) δ 7.72-7.53 (m, 1H),7.52-7.45 (m, 1H), 7.43-7.19 (m, 6H), 7.10 (d, J = 8.2 Hz, 1H), 5.35(dd, J = 12.5, 5.4 Hz, 1H), 4.62-4.45 (m, 3H), 4.39-4.34 (m, 4H),3.68-3.53 (m, 5H), 3.52 (dd, J = 6.2, 2.6 Hz, 1H), 3.44 (d, J = 4.0 Hz,1H), 3.42 (s, 3H), 2.9 (ddd, J = 18.9, 14.3, 5.1 Hz, 1H), 2.87-2.77 (m,2H), 2.68 (s, 2H), 2.32-2.15 (m, 2H), 2.05 (s, 2H), 2.03-1.92 (m, 1H),1.59-1.50 (m, 1H), 1.45 (s, 9H), 1.18 (dd, J = 6.2, 2.7 Hz, 3H). B-3-10

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[[5-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)pentyl] oxy]prop-1-yn-1- yl)phenyl]methoxy]pentan-3- yl]carbamate 772.5 (400 MHz, CD₃OD) δ 7.39 (d, J = 7.9 Hz,2H), 7.33 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 7.7, 1.3 Hz, 1H) 7.13 (d, J= 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.41 (d, J = 9.7 Hz, 1H), 5.35(dd, J = 12.2, 5.4 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.1Hz, 1H), 4.44 (s, 2H), 4.36 (s, 2H), 3.76 (s, 2H), 3.66-3.62 (m, 3H),3.58 (s, 2H), 3.54-3.47 (m, 2H), 2.97-2.77 (m, 2H), 2.32-2.14 (m, 2H),1.97 (s, 1H), 1.70-1.68 (m, 5H), 1.59-1.49 (m, 3H), 1.44 (s, 9H), 1.18(d, J = 6.3 Hz, 3H). B-3-11

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[[6-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro- 1H-1,3-benzodiazol-5- yl]prop-2-yn-1- yl]oxy)hexyl]oxy] prop-1-yn-1-yl)phenyl]methoxy] pentan-3- yl]carbamate 786.5 (400 MHz, DMSO-d₆) δ11.12 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34-7.30 (m, 5H), 7.22 (s,1H), 7.19-7.12 (m, 2H), 5.39 (dd, J = 12.7, 5.3 Hz, 1H), 4.53-4.40 (m,3H), 4.35 (d, J = 3.4 Hz, 4H), 3.52-3.54 (m, 4H), 2.95-2.83 (m, 1H),2.76-2.59 (m, 2H), 2.07- 2.01 (m, 4H), 1.92 (s, 1H), 1.77 (s, 1H),1.60-1.44 (m, 6H), 1.38 (s, 12H), 1.09-1.06 (m, 5H). B-3-12

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[[6-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)hexyl]oxy] prop-1-yn-1- yl)phenyl]methoxy]pentan-3- yl]carbamate 786.5 (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.40(d, J = 7.9 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.22 (s, 1H), 7.18 (d, J= 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.69(s, 1H), 6.63 (d, J = 9.1 Hz, 1H), 5.41 (dd, J = 12.6, 5.4 Hz, 1H),4.54- 4.44 (m, 2H), 4.42 (s, 2H), 4.34 (s, 2H), 3.563.37 (m, 7H), 2.90(ddd, J = 16.9, 12.6, 5.0 Hz, 1H), 2.77-2.57 (m, 2H), 2.13-1.98 (m, 3H),1.83-1.72 (m, 1H), 1.61- 1.42 (m, 6H), 1.38-1.35 (m, 14H), 1.07 (d, J =6.0 Hz, 3H). B-3-13

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[[6-([3-[3- methyl-1-(1-methyl-2,6- dioxopiperidin-3- yl)-2-oxo-1,3- benzodiazol-5- yl]prop-2-yn-1- yl]oxy)hexyl]oxy] prop-1-yn-1- yl)phenyl]methoxy] pentan-3-yl]carbamate 800.6 (400 MHz, DMSO-d₆) δ 7.40 (d, J = 8.0 Hz, 2H),7.36-7.32 (m, 3H), 7.21 (s, 1H), 7.15 (d, J = 1.1 Hz, 2H), 6.67 (s, 1H),6.66- 6.59 (m, 1H), 5.46 (dd, J = 12.9, 5.3 Hz, 1H), 4.55-4.43 (m, 2H),4.37-4.34 (m, 4H), 3.52-3.48 (m, 4H), 3.41 (dt, J = 12.1, 5.9 Hz, 1H),3.04 (s, 3H), 3.02-2.91 (m, 1H), 2.81 (s, 1H), 2.79-2.67 (m, 2H),2.10-1.99 (m, 1H), 1.92 (s, 1H), 1.78 (s, 1H), 1.55 (d, J = 6.7 Hz, 2H),1.40-1.32 (m, 14H), 1.07 (d, J = 6.0 Hz, 3H). B-3-14

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[[7-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]prop-2-yn-1- yl]oxy)hexyl]oxy] prop-1-yn-1- yl)phenyl]methoxy]pentan-3- yl]carbamate 800.4 (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.40(d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.3 Hz, 3H), 7.22 (s, 1H), 7.19-7.10(m, 2H), 6.68 (s, 1H), 6.63 (d, J = 9.2 Hz, 1H), 5.39 (dd, J = 12.6, 5.4Hz, 1H), 4.55-4.43 (m, 2H), 4.34 (d, J = 3.7 Hz, 4H), 3.52-3.48 (m, 4H),3.42 ( q, J = 5.7 Hz, 1H), 2.96- 2.84 (m, 1H), 2.77-2.60 (m, 2H),2.05-2.01 (m, 7H), 1.77 (s, 1H), 1.55-1.52 (m, 5H), 1.36-3.30 (m, 15H,1.07 (d, J = 6.1 Hz, 3H). B-3-15

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[[8-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]prop-2-yn-1- yl]oxy)octyl]oxy] prop-1-yn-1- yl)phenyl]methoxy] pentan-3-yl]carbamate 814.5 (400 MHz, CDCl₃) δ 8.46 (s, 1H), 7.44 (d, J = 7.9 Hz,2H), 7.27 (s, 2H), 7.24-7.19 (m, 1H), 7.13 (d, J = 1.4 Hz, 1H), 6.77 (d,J = 8.2 Hz, 1H), 5.21 (dd, J = 12.6, 5.3 Hz, 1H), 4.87 (d, J = 9.5 Hz,1H), 4.60 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.37 (s, 4H),4.35-4.32 (m, 6H), 3.68 (s, 1H), 3.61-3.56 (m, 4H), 3.44 (s, 3H), 2.96(d, J = 16.6 Hz, 1H), 2.89-2.73 (m, 2H), 2.37-2.22 (m, 4H), 1.75-1.71(m, 5H), 1.66-1.61 (m, 5H), 1.45 (s, 9H), 1.37 (s, 3H). B-3-16

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[2-[2-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro- 1H-1,3-benzodiazol-5- yl]prop-2-yn-1- yl]oxy)ethoxy] ethoxy]prop-1-yn- 1-yl)phenyl]methoxy] pentan-3- yl]carbamate 774.5 (400 MHz, DMSO-d₆) δ11.14 (s, 1H), 7.55-7.49 (m, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.36-7.28(m, 4H), 7.24 (s, 1H), 7.20-7.11 (m, 2H), 6.73-6.62 (m, 3H), 5.40 (dd, J= 12.8, 5.3 Hz, 1H), 3.70- 3.52 (m, 8H), 3.34 (s, 6H), 2.96- 2.84 (m,1H), 2.78-2.58 (m, 2H), 1.38 (s, 13H), 1.08-1.06 (m, 5H). B-3-17

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[2-[2-([3-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]prop-2-yn-1- yl]oxy)ethoxy] ethoxy]prop-1-yn- 1- yl)phenyl]methoxy]pentan-3- yl]carbamate 774.5 (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.41(d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.24- 7.11 (m, 3H), 7.03(t, J = 7.9 Hz, 1H), 6.74-6.57 (m, 2H), 5.76 (s, 1H), 5.40 (dd, J =12.7, 5.3 Hz, 1H), 4.50-4.46 (m, 4H), 4.40 (s, 2H), 3.71-3.34 (m, 13H),2.96- 2.83 (m, 1H), 2.78-2.60 (m, 2H), 2.13-1.96 (m, 3H), 1.77 (s, 1H),1.38 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H). B-3-18

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [16-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro- 1H-1,3-benzodiazol-5- yl]-4,7,10,13- tetraoxahexadeca- 1,15-diyn-1-yl]phenyl)methoxy] pentan-3- yl]carbamate 818.5 (400 MHz, DMSO-d₆) δ11.13 (s, 1H), 7.66-7.52 (m, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.37-7.28(m, 3H), 7.27-7.10 (m, 3H), 6.77-6.58 (m, 2H), 5.40 (dd, J = 12.7, 5.3Hz, 1H), 4.54-4.45 (m, 2H), 4.42-4.38 (m, 4H), 3.65- 3.61 (m, 4H),3.59-3.57 (m, 4H), 3.47-3.38 (m, 2H), 3.34 (s, 3H), 2.95-2.82 (m, 1H),2.75-2.58 (m, 2H), 2.08-1.97 (m, 3H), 1.77 (s, 1H), 1.56-1.44 (m, 1H),1.38 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H). B-3-19

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(3- [1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]prop-2-yn-1- yl]oxy)pentan-3-yl]carbamate 542.3 (400 MHz, CD₃OD) δ 7.39 (d, J = 1.8 Hz, 1H),7.32.-721 (m, 1H), 7.08 (d, J = 8.3 Hz, 1H), 5.34 (d, J = 9.8 Hz, 1H),4.54- 4.38 (m, 1H), 4.31 (d, J = 5.6 Hz, 1H), 3.74 (q, J = 6.2 Hz, 1H),3.62 (p, J = 6.3 Hz, 1H), 3.43 (s, 3H), 3.02-2.75 (m, 4H), 2.37-2.13 (m,2H), 2.12-1.85 (m, 1H), 1.71-1.53 (m, 1H), 1.45 (s, 9H), 1.19 (d, J =6.3 Hz, 3H). B-4-1

3-(5-[3-[(5- hydroxypentyl) oxy]prop-1-yn-1- yl]-3-methyl-2- oxo-1,3-benzodiazol-1- yl)piperidine-2,6- dione 400.3 (400 MHz, DMSO-d₆) δ 11.12(s, 1H), 7.33 (d, J = 1.4 Hz, 1H), 7.21-7.09 (m, 2H), 5.39 (dd, J =12.6, 5.4 Hz, 1H), 4.35 (d, J = 3.0 Hz, 3H), 3.51 (t, J = 6.5 Hz, 2H),3.40 (q, J = 6.1 Hz, 2H), 3.32 (s, 1H), 2.98-2.82 (m, 1H), 2.78-2.60 (m,2H), 2.09-2.00 (m, 2H), 1.55 (p, J = 6.8 Hz, 2H), 1.48-1.41 (m, 2H),1.36 (qd, J = 8.8, 7.3, 2.9 Hz, 2H). B-4-2

3-(4-[3-[(5- hydroxypentyl) oxy]prop-1-yn-1- yl]-3-methyl-2- oxo-1,3-benzodiazol-1- yl)piperidine-2,6- dione 400.2 (400 MHz, DMSO-d₆) δ 11.13(s, 1H), 7.19-7.13 (m, 2H), 7.04 (t, J = 7.9 Hz, 1H), 5.41 (dd, J =12.6, 5.3 Hz, 1H), 4.42 (s, 2H), 4.35 (t, J = 5.1 Hz, 1H), 3.65 (s, 3H),3.53 (t, J = 6.5 Hz, 2H), 3.39 (q, J = 5.9 Hz, 2H), 2.90 (ddd, J = 17.0,12.8, 5.2 Hz, 1H), 2.78-2.58 (m, 2H), 2.09-1.98 (m, 1H), 1.56 (p, J =6.8 Hz, 2H), 1.47-1.39 (m, 2H), 1.36 (td, J = 9.0, 5.2 Hz, 2H). B-4-3

3-(4-[3-[(5- hydroxyethoxy) prop-1-yn-1-yl]-3- yl]-3-methyl-2-methyl-2-oxo- 1,3-benzodiazol- 1-yl)piperidine- 2,6-dione 358.2 (400MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.20-7.16 (m, 1H), 7.15- 7.11 (m, 1H),7.03 (td, J = 7.9, 2.9 Hz, 1H), 5.44-5.36 (m, 1H), 4.67 (p, J = 2.7 Hz,1H), 4.46 (d, J = 2.8 Hz, 2H), 3.58-3.54 (m, 4H), 3.31 (s, 2H), 2.89 (t,J = 15.2 Hz, 1H), 2.79-2.58 (m, 3H), 2.03 (t, J = 7.4 Hz, 1H). B-4-4

3-[4-(4- hydroxybut-1-yn-) 1-yl)-3-methyl-2- oxo-1,3- benzodiazol-1-yl]piperidine-2,6- dione 328.3 (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.12(dd, J = 7.9, 1.2 Hz, 1H), 7.06 (dd, J = 7.8 Hz, 1H), 1H), 6.99 (t, J =7.8z, 1H), 5.39 (dd, J = 12.6, 5.4 Hz, 1H), 4.93 (t, J = 5.5 Hz, 1H),3.65 (s, 3H), 3.63 (t, J = 5.9 Hz, 2H), 2.95-2.84 m, 1H), 2.72 (td, J =12.9, 4.4 Hz, 1H) 2.63 (q, J = 6.7, 6.2 Hz, 3H), 2.06-1.98 (m, 1H).B-4-5

3-[4-(5- hydroxypent-1- yn-1-yl)-3- methyl-2-oxo- 1,3-benzodiazol-1-yl]piperidine- 2,6-dione 342.3 (400 MHz, DMSO-d₆) δ 11.12 (s, 1H),7.12 (dd, J = 7.7, 1.2 Hz, 1H), 7.08-7.04 (m, 1H), 6.99 (t, J = 7.8 Hz,1H), 5.39 (dd, J = 12.7, 5.3 Hz, 1H), 4.56 (t, J = 5.1 Hz, 1H), 3.64 (s,3H), 3.53 (q, J = 6.1 Hz, 2H), 3.43 (tt, J = 11.6, 5.5 Hz, 1H),2.96-2.83 (m, 1H), 2.77-2.59 (m, 2H), 2.03 (ddt, J = 10.9, 5.7m 2.7 Hz,1H), 1.79-1.69 (m, 2H) 1.66-1.44 (m, 1H). B-4-6

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(5-hydroxypentyl)oxy[prop-1- yn-1- yl]phenyl)methoxy] pentan-3- yl]carbamate 477.4 (400MHz, DMSO-d₆) δ 7.41 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.22(s, 1H), 6.68 (s, 1H), 6.63 (d, J = 9.1 Hz, 1H), 4.55-4.44 (m, 2H), 4.35(s, 2H), 4.35 (d, J = 10.3 Hz, 1H), 3.50 (t, J = 6.5 Hz, 2H), 3.46-3.36(m, 3H), 2.04 (ddd, J = 22.3, 11.6, 6.3 Hz, 1H), 1.78 (s, 1H), 1.54 (h,J = 7.8, 7.3 Hz, 2H), 1.48 (s, 2H), 1.47-1.40 (m, 2H), 1.38 (s, 7H),1.39-1.30 (m, 5H), 1.07 (d, J = 6.0 Hz, 3H). B-4-7

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- (4-hydroxybut)-1- yn-1-yl]phenyl)methoxy] pentan-3- yl]carbamate 405.3 (400 MHz, DMSO-d₆) δ7.35- 7.30 (m, 4H), 7.22 (s, 1H), 6.68 (s, 1H), 6.62 (d, J = 9.2 Hz,1H), 4.88 (t, J = 5.6 Hz, 1H), 4.53- 4.42 (m, 2H), 3.58 (q, J = 6.7 Hz,2H), 3.47-3.43 (m, 1H), 3.40 (d, J = 5.9 Hz, 1H), 3.32 (s, 1H), 2.55 (t,J = 6.9z, 2H), 2.12- 1.95 (m, 2H), 1.82-1.71 (m, 1H), 1.52-1.43 (m, 1H),1.38 (s, 8H), 1.06 (d, J = 6.1 Hz, 3H). B-4-8

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[[4-(5- hydroxypent-1- yn-1-yl]phenyl)methoxy] pentan-3- yl]carbamate 419.3 (400 MHz, DMSO-d₆) δ7.38 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.58 (s, 1H), 5.59(s, 1H) 4.86 (d, J = 9.7 Hz, 1H) 4.59 (d, J = 12.0 Hz, 1H), 4.40 (d, J =11.9 Hz, 1H), 3.84 (t, J = 6.1 Hz, 2H), 3.73-3.57 (m, 2H), 2.56 (t, J =7.0 Hz, 2H), 2.36-2.22 (m, 3H), 1.98 (t, J = 7.6 Hz, 1H), 1.88 (p, J =6.6 Hz, 2H), 1.76- 1.64 (m, 1H), 1.45 (s, 9H), 1.21 (d, J = 6.3 Hz, 3H).B-4-9

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (3-[2-[2-[(2- hydroxyethoxy)ethoxy]ethoxy]prop- 1-yn-1- yl]phenyl]methoxy] pentan-3- yl]carbamate523.4 (400 MHz, CDCl₃) δ 7.46-7.42 (m, 2H), 7.29 (s, 1H), 7.27 (s, 1H),6.43 (s, 1H), 5.47 (s, 1H), 4.86 (d, J = 9.7 Hz, 1H), 4.60 (d, J = 12.0Hz, 1H), 4.46-4.43 (m, 3H), 3.83-3.78 (m, 2H), 3.77- 3.74 (m, 4H), 3.71(s, 5H), 3.66- 3.60 (m, 3H), 2.38-2.22 (m, 3H), 2.04-1.94 (m, 1H),1.72-1.69 (m, 1H), 1.45 (s, 9H), 1.21 (d, J = 6.3 Hz, 3H). B-4-10

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (1-hydroxy- 3,6,9,12-tetraoxapentadec- 14-yn-15- yl)phenyl]methoxy] pentan-3- yl]carbamate567.4 (400 MHz, CDCl₃) δ 7.46-7.41 (m, 2H), 7.29 (s, 1H), 7.27 (s, 1H),6.56 (s, 1H), 5.64 (s, 1H), 4.87 (d, J = 9.7 Hz, 1H), 4.61 (d, J = 12.0Hz, 1H), 4.44 (d, J = 5.3 Hz, 3H), 3.82-3.77 (m, 2H), 3.77-3.72 (m, 4H),3.72-3.66 (m, 9H), 3.65-3.61 (m, 3H), 2.41- 2.21 (m, 2H), 2.03 (s, 2H),1.76- 1.65 (m, 1H), 1.45 (s, 9H), 1.22 (d, J = 6.3 Hz, 3H). B-4-11

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (1-hydroxy- 3,6,9,12,15-pentaoxaoctadec- 17-yn-18- yl)phenyl]methoxy] pentan-3- yl]carbamate611.3 (400 MHz, CDCl₃) δ 7.45-7.41 (m, 2H), 7.29 (s, 1H), 7.27 (s, 1H),6.40 (s, 1H), 5.50 (s, 1H), 4.86 (d, J = 9.7 Hz, 1H), 4.60 (d, J = 12.0Hz, 1H), 4.44 (d, J = 3.5 Hz, 2H), 3.81-3.77 (m, 2H), 3.76-3.73 (m, 4H),3.71-3.68 (m, 14H), 3.63 (t, J = 4.5 Hz, 3H), 2.30 (q, J = 6.1, 5.0 Hz,3H), 2.02-1.98 (m, 1H), 1.71 (dt, J = 13.8, 6.2 Hz, 1H), 1.46 (s, 9H),1.22 (d, J = 6.3 Hz, 3H). B-4-12

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (3- hydroxyprop-1- yn-1-yl)phenyl]methoxy] pentan-3- yl]carbamate [(M + Na)]⁺ = 413.3 (400 MHz,DMSO-d₆) δ 7.40- 7.31 (m, 4H), 7.22 (s, 1H), 6.71- 6.61 (m, 2H), 5.32(t, J = 6.0 Hz, 1H), 4.55-4.44 (m, 2H), 4.30 (d, J = 6.0 Hz, 2H), 3.42(dd, J = 14.0, 7.9 Hz, 2H), 2.03 (tq, J = 14.8, 8.2, 6.7 Hz, 2H),1.83-1.43 (m, 2H), 1.38 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H). B-4-13

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(2- hydroxyethoxy)prop-1-yn-1- yl]phenyl]methoxy) pentan-3- yl]carbamate 435.4 (400 MHz,CDCl₃) δ 7.44 (d, J = 7.9 Hz, 2H), 7.29 (s, 2H), 6.36 (s, 1H), 5.46 (s,1H), 4.85 (d, J = 9.7 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.45 (d, J =4.1 Hz, 2H), 3.82 (d, J = 5.5 Hz, 2H), 3.74 (dd, J = 5.1, 3.8 Hz, 2H),3.70-3.58 (m, 2H), 2.30 (s, 2H), 1.99 (d, J = 6.7 Hz, 2H), 1.45 (s, 9H,1.21 (d, J = 6.3 Hz, 3H). B-4-14

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(2- hydroxyethoxy)prop-1-yn-1- yl]phenyl]methoxy) pentan-3- yl]carbamate 479.3 (400 MHz,DMSO-d₆) δ 7.41 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.21 (s,1H), 6.68 (s, 1H), 6.63 (d, J = 9.0 Hz, 1H), 4.58 (t, J = 5.5 Hz, 1H),4.55- 4.44 (m, 2H), 4.40 (s, 2H), 3.64 (dd, J = 5.9, 3.5 Hz, 2H), 3.58(dd, J = 6.2, 3.5 Hz, 2H), 3.54- 3.38 (m, 5H), 3.31 (s, 1H), 2.08 (s,2H), 1.50 (dd, J = 14.2, 9.2 Hz, 1H), 1.38 (s, 9H), 1.07 (d, J = 6.1 Hz,3H). B-4-15

3-[5-(4- hydroxypentbut-1-yn- 1-yl)-3-methyl-2- oxo-1,3- benzodiazol-1-yl]piperidine-2,6- dione 328.2 (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.25(d, J = 1.3 Hz, 1H), 7.10 (d, J = 1.1 Hz, 2H), 5.38 (dd, J = 12.8, 5.3Hz, 1H), 4.88 (s, 1H), 3.60 (d, J = 7.7 Hz, 2H), 3.34 (s, 3H), 2.95-2.83(m, 1H), 2.75-2.59 (m, 2H), 2.55 (t, J = 3.5 Hz, 2H), 2.03 (ddd, J =10.2, 5.9,3.7 Hz, 1H). B-4-16

3-[5-(6- hydroxyhex-1- yn-1-yl)-3- methyl-2-oxo- 1,3-benzodiazol-1-yl]piperidine- 2,6-dione 356.2 (400 MHz, DMSO-d₆) δ 11.11 (s, 1H),7.24 (s, 1H), 7.09 (s, 2H), 5.368 (dd, J = 12.8, 5.4 Hz, 1H), 4.43 (s,1H), 3.46 (d, J = 5.5 Hz, 2H), 3.34 (s, 3H), 2.97- 2.83 (m, 1H),2.77-2.58 (m, 2H), 2.47-2.39 (m, 2H), 2.07-1.97 (m, 1H), 1.64-1.54 (m,4H). B-4-17

3-[5-(7- hydroxyhept-1- yn-1-yl)-3- methyl-2-oxo- 1,3-benzodiazol-1-yl]piperidine- 2,6-dione  370.30 (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.15(dd, J = 8.1, 1.5 Hz, 1H), 7.08 (d, J = 1.4 Hz, 1H), 6.73 (d, J = 8.1Hz, 1H), 5.20 (dd, J = 12.7, 5.4 Hz, 1H), 3.70 (t, J = 6.5 Hz, 2H), 3.43(s, 3H), 3.02-2.90 (m, 1H), 2.85-2.73 (m, 2H), 2.45 (t, J = 7.0 Hz, 2H),2.3-2.19 (m, 1H), 1.79-1.49 (m, 6H).

Step 4. Tert-butylN-[(3S,4R)-1-Carbamoyl-4-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)pentan-3-yl]carbamate(Intermediate B). To a solution of tert-butylN-[(3S,4R)-1-carbamoyl-4-[(4-[3-[2-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]prop-2-yn-1l-yl]oxy)ethoxy]prop-1-yn-1-yl]phenyl)methoxy]pentan-3-yl]carbamate(490 mg, 0.67 mmol) in THF (20 mL) was added palladium on charcoal (400mg, 10% w/w) at room temperature under nitrogen atmosphere. Theresulting mixture was purged with hydrogen for 3 times and stirred for 4hours at room temperature under hydrogen atmosphere (2 atm.). Thereaction mixture was filtered through a celite pad. The filtrate wasconcentrated under reduced pressure to afford the title compound as adark brown solid (410 mg, 830%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (d,J=10.8 Hz, 1H), 7.76-7.61 (m, 1H), 7.37-7.26 (m, 1H), 7.19-7.14 (m, 4H),7.06-6.93 (m, 2H), 6.86 (d, J=12.5 Hz, 2H), 6.72-6.56 (m, 2H), 5.34 (dd,J=12.7, 5.4 Hz, 1H), 4.53-4.33 (m, 2H), 4.21 (dt, J=13.6, 6.7 Hz, 1H),3.66-3.33 (m, 12H), 2.89 (d, J=12.6 Hz, 1H), 2.73-2.54 (m, 5H), 2.47 (s,1H), 2.17 (d, J=13.3 Hz, 1H), 2.02-1.97 (m, 3H), 1.88-1.69 (m, 9H), 1.64(dd, J=14.5, 7.0 Hz, 1H), 1.05 (dt, J=11.3, 6.4 Hz, 3H), 0.91-0.82 (m,2H); MS (ESI, m/z): [(M−1)]⁺=736.40.

The intermediates in Table 16 below were prepared according to Step 4 ofthe procedure to prepare Intermediate B.

TABLE 16 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR B1

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (3-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]methoxy]pro- pyl)phenyl]meth- oxy]pentan-3- yl]carbamate 666.4 (400MHz, DMSO-d₆) δ 11.04 (s, 1H), 7.18-6.94 (m, 7H), 6.61-6.54 (m, 2H),5.34 (s, 1H), 4.63 (s, 2H), 4.36 (s, 2H), 3.38-3.35 (m, 3H), 3.53 (s,3H), 3.26 (s, 2H), 2.84 (s, 1H), 2.74- 2.66 (m, 5H), 2.02-1.95 (m, 3H),1.77 (s, 3H), 1.39-1.28 (m, 9H), 1.00 (s, 3H). B2

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (3-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]propoxy]pro- pyl)phenyl]meth- oxy]pentan-3- yl]carbamate 694.5 (400MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.24 (d, J = 7.9 Hz, 2H), 7.20 (s, 1H),7.15 (d, J = 7.7 Hz, 2H), 6.96 (dd, J = 5.1, 3.3 Hz, 2H), 6.87 (dd, J =5.3, 3.7 Hz, 1H), 6.69-6.64 (m, 1H), 6.60 (d, J = 9.0 Hz, 1H), 5.36 (dd,J = 12.6, 5.3 Hz, 1H), 4.49-4.37 (m, 2H), 3.59-3.56 (m, 3H), 3.44-3.37(m, 4H), 3.01-2.93 (m, 2H), 2.92-2.82 (m, 1H), 2.77-2.58 (m, 4H),2.09-2.06 (m, 3H), 1.98 (d, J = 14.4 Hz, 1H), 1.92-1.75 (m, 5H), 1.45(s, 2H), 1.41-1.35 (m, 9H), 1.06 (d, J = 5.8 Hz, 3H). B3

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(2-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]propoxy]eth- oxy)pro- pyl]phenyl]meth- oxy)pentan-3- yl]carbamate738.5 (400 MHz, CD₃OD) δ 7.26 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz,2H), 7.03 (q, J = 7.5, 6.9 Hz, 1H), 6.98 (d, J = 7.3 Hz, 2H), 6.40 (d, J= 9.5 Hz, 1H), 5.33 (dd, J = 12.2, 5.6 Hz, 1H), 4.53 (d, J = 11.4 Hz,1H), 4.45 (d, J = 11.5 Hz, 1H), 3.67 (s, 3H), 3.59 (s, 1H), 3.63-3.45(m, 10H), 3.07 (q, J = 8.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.87-2.77 (m,2H), 2.70 (t, J = 7.6 Hz, 2H), 2.30- 2.20 (m, 1H), 2.15 (dt, J = 10.8,6.4 Hz, 1H), 1.96 (t, J = 6.4 Hz, 1H), 1.92-1.84 (4H), 1.60 (s, 1H),1.45 (s, 8H), 1.17 (d, J = 6.2 Hz, 3H). B4

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(2-[3-[3-methyl-1-(1-methyl-2,6- dioxopiperidin-3- yl)-2-oxo-1,3- benzodiazol-4-yl]propoxy]eth- oxy)pro- pyl]phenyl]meth- oxy)pentan-3- yl]carbamate752.6 (400 MHz, DMSO-d₆) 7.31 (q, J = 7.0, 5.7 Hz, 1H), 7.22-7.14 (m,4H), 6.99-6.85 (m, 3H), 6.66 (s, 1H), 6.63- 6.54 (m, 1H), 5.46-5.38 (m,1H), 4.41 (s, 2H), 3.59-3.49 (m, 3H), 3.52-3.36 (m, 6H), 3.32 (s, 1H),3.03 (d, J = 7.4 Hz, 2H), 2.99-2.91 (m, 3H), 2.74 (s, 1H), 2.60 (q, J =7.9 Hz, 1H), 2.18 (d, J = 8.3 Hz, 1H), 2.01 (s, 3H), 1.83 (d, J = 7.1Hz, 1H), 1.80 (s, 3H), 1.77 (t, J = 7.3 Hz, 2H), 1.46 (s, 1H), 1.39-1.32 (m, 13H), 1.04 (t, J = 6.5 Hz, 3H). B5

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(3-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]propoxy]pro- poxy)pro- pyl]phenyl]meth- oxy)pentan-3- yl]carbamate752.5 (400 MHz, CDCl₃) δ 8.73 (s, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.17(d, J = 7.7 Hz, 2H), 6.94-6.86 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 5.23(dd, J = 12.7, 5.3 Hz, 1H), 4.92 (d, J = 9.7 Hz, 1H), 4.58 (d, J = 11.5Hz, 1H), 4.39 (dd, J = 11.4, 2.0 Hz, 1H), 3.68 (s, 1H), 3.64-3.58 (m,1H), 3.56-3.51 (m, 5H), 3.48-3.37 (m, 7H), 2.92 (s, 1H), 2.86 (dd, J =13.1, 5.1 Hz, 1H), 2.74-2.62 (m, 5H), 2.32-2.21 (m, 3H), 1.95-1.87 (m,6H), 1.76-1.65 (m, 1H), 1.45 (s, 9H), 1.28 (s, 1H), 1.21 (dd, J = 6.3,1.4 Hz, 3H). B6

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(3 -[3-[1 -(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]propoxy]pro- poxy)pro- pyl]phenyl]meth- oxy)pentan-3- yl]carbamate752.5 (400 MHz, CD₃OD) δ 7.7.24-7.13 (m, 4H), 6.97 (s, 3H), 5.33 (s,1H), 4.53- 4.48 (m, 2H), 3.67 (s, 3H), 3.52 (s, 6H), 3.44 (s, 3H), 3.07(s, 3H), 2.82 (s, 2H), 2.68 (s, 2H), 2.24 (s, 3H), 1.87 (s, 8H), 1.60(s, 1H), 1.44 (s, 9H), 1.16 (s, 3H). B7

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(4-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol- 5-yl]pro-poxy]butoxy)pro- pyl]phenyl]meth- oxy)pentan-3- yl]carbamate 766.5 (400MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.25-7.19 (m, 2H), 7.14 (d, J = 7.8 Hz,1H), 7.08-6.98 (m, 2H), 6.87 (dd, J = 8.0, 1.5 Hz, 1H), 6.71-6.56 (m,1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 4.47-4.39 (m, 1H), 3.63-3.59 (m,6H), 3.38-3.35 (m, 6H), 2.97-2.84 (m, 1H), 2.77-2.55 (m, 5H), 2.14-1.94(m, 3H), 1.87-1.72 (m, 12H), 1.63-1.50 (m, 4H), 1.39-1.35 (m, 9H), 1.03(dd, J = 18.7, 6.2 Hz, 3H). B8

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(4-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]pro-poxy]butoxy)pro- pyl]phenyl]meth- oxy)pentan-3- yl]carbamate 766.5 (400MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.25-7.21 (m, 3H), 7.14 (d, J = 7.8 Hz,2H), 6.99-6.92 (m, 2H), 6.90- 6.83 (m, 1H), 6.68 (s, 1H), 6.66-6.57 (m,1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 4.48-4.37 (m, 2H), 3.47-3.30 (m,10H), 3.00-2.92 (m, 2H), 2.92-2.83 (m, 1H), 2.72 (td, J = 12.8, 4.3 Hz,1H), 2.63 (d, J = 10.4 Hz, 1H), 2.59 (d, J = 7.7 Hz, 2H), 2.19 (s, 1H),2.02 (tdd, J = 15.7 , 10.0, 5.4 Hz, 2H), 1.82- 1.74 (m, 6H), 1.59-1.52(m, 4H), 1.40-1.33 (m, 12H), 1.05 (d, J = 6.1 Hz, 3H). B9

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(5-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]pro-poxy]pentyl)oxy]pro- pyl]phenyl)meth- oxy]pentan-3- yl]carbamate 780.7(400 MHz, CD₃OD) δ 7.26 (d, J = 7.7 Hz, 2H), 7.15 (d, J = 7.7 Hz, 2H),7.06-6.93 (m, 3H), 5.31 (dd, J = 12.4, 5.3 Hz, 1H), 4.54 (d, J = 11.4Hz, 1H), 4.47 (d, J = 11.6 Hz, 1H), 3.58 (s, 1H), 3.49-3.39 (m, 11H),2.96-2.86 (m, 1H), 2.81-2.76 (m, 4H), 2.67 (t, J = 7.7 Hz, 2H), 2.25 (q,J = 9.2 Hz, 1H), 2.17 (s, 1H), 1.92-1.85 (m, 4H), 1.64- 1.61 (m, 6H),1.50 (d, J = 6.8 Hz, 1H), 1.45 (s, 11H), 1.31 (s, 1H), 1.16 (d, J = 6.2Hz, 3H). B10

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(5-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]pro-poxy]pentyl)oxy]pro- pyl]phenyl)meth- oxy]pentan-3- yl]carbamate 780.7(400 MHz, CD₃OD) δ 7.25 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H),7.08-7.00 (m, 1H), 6.97 (t, J = 7.2 Hz, 2H), 6.40 (d, J = 9.4 Hz, 1H),5.33 (dd, J = 12.2, 5.5 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H), 4.46 (d, J =11.5 Hz, 1H), 3.70-3.66 (m, 3H), 3.58 (s, 1H), 3.55-3.39 (m, 8H), 3.08(dd, J = 8.9, 6.7 Hz, 2H), 3.01-2.87 (m, 1H), 2.85- 2.77 (m, 2H), 2.68(dd, J = 8.4, 6.8 Hz, 2H), 2.31-2.10 (m, 2H), 1.93 (s, 3H), 1.99-1.81(m, 2H), 1.63 (s, 6H), 1.51 (d, J = 6.8 Hz, 1H), 1.45 (s, 9H), 1.17 (d,J = 6.2 Hz, 3H). B11

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(6-[3-[1-[2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]propoxy]hex- yl)oxy]pro- pyl]phenyl)meth- oxy]pentan-3- yl]carbamate794.5 (400 MHz, CDCl₃) δ 8.43 (s, 1H), 7.27-7.24 (m, 3H), 7.18 (d, J =7.8 Hz, 2H), 6.94-6.86 (m, 3H), 6.73 (d, J = 8.0 Hz, 1H), 5.93 (s, 1H),5.23 (dd, J = 12.5, 5.2 Hz, 1H), 4.93 (d, J = 9.4 Hz, 1H), 4.59 (d, J =11.4 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 3.63 (s, 2H), 3.45-3.42 (m,8H), 2.94 (s, 1H), 2.76- 2.67 (m, 6H), 2.36-2.21 (m, 4H), 1.92-1.86 (m,7H), 1.46 (m, 17H), 1.22 (d, J = 6.1 Hz, 3H). B12

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(6-[3-[1-[2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]propoxy]hex- yl)oxy]propyl]phen- yl)methoxy]pentan- 3-yl]carbamate794.7 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.25-7.19 (m, 3H), 7.13 (d, J= 7.8 Hz, 2H), 7.00-6.93 (m, 2H), 6.88 (s, 1H), 6.63 (dd, J = 23.7, 11.5Hz, 2H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H), 4.48-4.37 (m, 2H), 3.64-3.57(m, 4H), 3.44-3.36 (m, 7H), 3.00-2.84 (m, 3H), 2.77-2.57 (m, 4H),2.11-1.96 (m, 3H), 1.83-1.76 (m, 6H), 1.53-1.49 (m, 5H), 1.39-1.34 (m,14H), 1.06 (d, J = 6.0 Hz, 3H). B13

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(6-[3-[3- methyl-1-(1-methyl-2,6- dioxopiperidin-3- yl)-2-oxo-1,3- benzodiazol-5-yl]propoxy]hex- yl)oxy]pro- pyl]phenyl)meth- oxy]pentan-3- yl]carbamate808.6 (400 MHz, DMSO-d₆) δ 7.23 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.8Hz, 2H), 7.06-6.98 (m, 2H), 6.90-6.82 (m, 2H), 6.67 (s, 1H), 6.65-6.56(m, 1H), 5.40 (dd, J = 13.0, 5.3 Hz, 1H), 4.48-4.37 (m, 2H), 3.43-3.29(m, 12H), 3.04 (s, 3H), 2.96 (dd, J = 13.2, 5.0 Hz, 1H), 2.80 (s, 1H),2.78-2.69 (m, 1H), 2.72- 2.63 (m, 2H), 2.62-2.57 (m, 3H), 2.19 (s, 1H),2.11-1.99 (m, 1H), 1.83-1.76 (m, 5H), 1.53 (d, J = 4.9 Hz, 1H), 1.50 (s,4H), 1.40-1.36 (m, 14H), 1.34 (s, 3H), 1.06 (d, J = 6.0 Hz, 3H). B14

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(7-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]propoxy]hep- tyl)oxy]pro- pyl]phenyl)meth- oxy]pentan- 3-yl]carbamate808.6 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.25-7.21 (m, 3H), 7.13 (d, J= 7.8 Hz, 2H), 7.05-6.97 (m, 2H), 6.89- 6.84 (m, 1H), 6.68 (s, 1H), 6.60(d, J = 9.2 Hz, 1H), 5.34 (dd, J = 12.6, 5.4 Hz, 1H), 4.48-4.38 (m, 2H),3.49-3.33 (m, 8H), 2.96-2.85 (m, 1H), 2.76-2.56 (m, 6H), 2.07-1.98 (m,3H), 1.87-1.72 (m, 6H), 1.57-1.42 (m, 6H), 1.41-1.26 (m, 18H), 1.06 (d,J = 6.0 Hz, 3H). B15

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(8-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]pro-poxy]octyl)oxy]pro- pyl]phenyl)meth- oxy]pentan-3- yl]carbamate 822.6(400 MHz, CDCl₃) δ 8.46 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H),7.18 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.95- 6.87 (m, 1H), 6.73 (d, J =8.0 Hz, 1H), 5.23 (dd, J = 12.6, 5.4 Hz, 1H), 4.92 (d, J = 9.6 Hz, 1H),4.59 (d, J = 11.4 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 4.36-4.31 (m, 5H),3.79-3.75 (m, 1H), 3.70-3.59 (m, 2H), 3.46-3.40 (m, 8H), 2.95 (d, J =16.9 Hz, 1H), 2.89-2.79 (m, 1H), 2.75-2.70 (m, 4H), 2.33 (d, J = 15.8Hz, 1H), 2.26 (dd, J = 7.9, 5.0 Hz, 1H), 1.93-1.87 (m, 4H), 1.81-1.69(m, 10H), 1.62-1.57 (m, 4H), 1.46 (s, 10H), 1.36 (s, 3H). B16

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[2-(2-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro- 1H-1,3-benzodiazol-5- yl]propoxy]eth- oxy)ethoxy]pro- pyl]phenyl)meth-oxy]pentan- 3-yl]carbamate 782.5 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.22 (d, J = 7.7 Hz, 3H), 7.13 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 1.4 Hz,1H), 7.00 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.68 (s, 1H),6.61 (d, J = 9.3 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.47-4.35 (m,2H), 3.58- 3.46 (m, 9H), 3.43-3.34 (m, 6H), 2.88 (d, J = 16.5 Hz, 1H),2.70-2.62 (m, 3H), 2.59 (t, J = 7.6 Hz, 2H), 2.09- 2.01 (m, 4H),1.82-1.75 (m, 5H), 1.38 (s, 12H), 1.05 (d, J = 6.0 Hz, 3H). B17

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[2-[2-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]propoxy]eth- oxy)ethoxy]pro- pyl]phenyl)meth- oxy]pentan-3-yl]carbamate 782.5 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.25-7.20 (m,3H), 7.13 (d, J = 7.8 Hz, 2H), 7.00-6.92 (m, 2H), 6.87 (dd, J = 5.8, 3.0Hz, 1H), 6.72-6.56 (m, 2H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 4.50-4.36(m, 2H), 3.58-3.42 (m, 14H), 3.39-3.36 (m, 3H), 3.02-2.83 (m, 3H),2.78-2.54 (m, 4H), 2.08-2.01 (m, 3H), 1.88-1.72 (m, 5H), 1.39-1.35 (m,10H), 1.05 (d, J = 6.0 Hz, 3H). B18

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [16-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro- 1H-1,3-benzodiazol-5-yl]- 4,7,10,13- tetraoxahexadecan- 1-yl]phenyl)meth-oxy]pentan-3- yl]carbamate 826.6 (400 MHz, CDCl₃) δ 8.47-8.45 (m, 1H),7.72-7.67 (m, 1H), 7.53 (d, J = 33.8 Hz, 1H), 7.24 (d, J = 7.7 Hz, 2H),7.17 (d, J = 7.7 Hz, 2H), 6.95-6.86 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H),5.79 (s, 1H), 5.27-5.17 (m, 1H), 4.94-4.92 (m, 1H), 4.58 (d, J = 11.4Hz, 1H), 4.38 (d, J = 11.5 Hz, 1H), 3.81-3.54 (m, 15H), 3.51-5.47 (m,4H), 3.44 (s, 3H), 2.96 (d, J = 16.9 Hz, 1H), 2.86 (d, J = 14.4 Hz, 1H),2.75-2.71 (m, 5H), 2.30-2.26 (m, 3H), 2.09-1.59 (m, 11H), 1.21 (d, J =6.0 Hz, 3H). B19

3-(5-[3-[(5- hydroxy- pentyl)oxy]pro- pyl]-3-methyl- 2-oxo-1,3-benzodiazol-1- yl)piperidine-2,6- dione 404.2 (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 7.07-6.97 (m, 2H), 6.87 (dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J= 12.7, 5.4 Hz, 1H), 4.35-4.33 (m, 1H), 3.43- 3.34 (m, 9H), 2.90 (ddd, J= 17.0, 12.9, 5.2 Hz, 1H), 2.79-2.58 (m, 4H), 2.06-1.95 (m, 1H),1.87-1.77 (m, 2H), 1.51 (dt, J = 14.0, 6.8 Hz, 2H), 1.46- 1.39 (m, 2H),1.38-1.30 (m, 2H). B20

3-(4-[3-[(5- hydroxy- pentyl)oxy]pro- pyl]-3-methyl- 2-oxo-1,3-benzodiazol-1- yl)piperidine-2,6- dione 404.3 (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 6.97 (d, J = 4.6 Hz, 2H), 6.88 (q, J = 4.4 Hz, 1H), 5.37 (dd, J= 12.5, 5.4 Hz, 1H), 4.34 (t, J = 5.2 Hz, 1H), 3.62-3.54 (m, 4H),3.43-3.38 (m, 4H), 3.01-2.83 (m, 3H), 2.77-2.58 (m, 2H), 2.05-1.95 (m,1H), 1.86-1.74 (m, 3H), 1.52 (p, J = 6.8 Hz, 2H), 1.43 (q, J = 6.8, 6.1Hz, 2H), 1.38-1.32 (m, 2H). B20

3-[4-[3-(2- hydroxyethoxy)pro- pyl]-3-methyl-2- oxo-1,3- benzodiazol-l-yl]piperidine-2,6- dione 362.2 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 6.97(d, J = 4.4 Hz, 2H), 6.89 (d, J = 4.7 Hz, 1H), 5.36 (dd, J = 12.6, 5.4Hz, 1H), 4.57 (dd, J = 6.1, 4.8 Hz, 1H), 3.63-3.39 (m, 9H), 3.00-2.84(m, 3H), 2.76-2.58 (m, 2H), 2.05-1.96 (m, 1H), 1.89-1.74 (m, 2H). B21

3-[4-(4- hydroxybutyl)-3- methyl-2-oxo-1,3- benzodiazol-l-yl]piperidine-2,6- dione 332.2 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.00-6.94 (m, 2H), 6.87 (dd, J = 5.2, 3.7 Hz, 1H), 5.37 (dd, J = 12.5,5.4 Hz, 1H), 4.40 (t, J = 5.2 Hz, 1H), 3.56 (s, 3H), 3.48-3.42 (m, 2H),2.90 (dd, J = 9.5, 6.0 Hz, 2H), 2.77-2.59 (m, 2H), 2.04-1.97 (m, 1H),1.79-1.74 (m, 1H), 1.63 (tt, J = 8.2, 5.8 Hz, 2H), 1.58-1.50 (m, 2H).B22

3-[4-(5- hydroxypentyl)-3- methyl-2-oxo-1,3- benzodiazol-1-yl]piperidine-2,6- dione 346.3 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),6.99-6.93 (m, 2H), 6.87 (q, J = 4.3 Hz, 1H), 5.36 (dd, J = 12.5, 5.4 Hz,1H), 4.35 (t, J = 5.1 Hz, 1H), 3.56 (s, 3H), 3.43-3.37 (m, 2H), 2.89 (t,J = 7.8 Hz, 2H), 2.72 (td, J = 12.8, 4.3 Hz, 1H), 2.66-2.58 (m, 1H),2.05-1.95 (m, 1H), 1.61 (p, J = 7.6 Hz, 2H), 1.47 (q, J = 7.2 Hz, 2H),1.41 (t, J = 7.8 Hz, 2H), 1.25 (s, 1H). B23

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[(5- hydroxy-pentyl)oxy]pro- pyl]phenyl)meth- oxy]pentan-3- yl]carbamate 481.4 (400MHz, DMSO-d₆) δ 7.24-7.22 (m, 3H), 7.14 (d, J = 7.7 Hz, 2H), 6.68 (s,1H), 6.66-6.57 (m, 1H), 4.49-4.38 (m, 2H), 4.34 (t, J = 5.2 Hz, 1H),3.61 (s, 1H), 3.46-3.29 (m, 9H), 2.60 (t, J = 7.6 Hz, 2H), 2.07-2.02 (m,1H), 1.80-1.75 (m, 4H), 1.50 (p, J = 6.7 Hz, 2H), 1.44 (d, J = 7.3 Hz,1H), 1.40-1.36 (m, 15H), 1.06 (d, J = 6.0 Hz, 3H). B24

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (4-hydroxy-butyl)phenyl]meth- oxy]pentan- 3-yl]carbamate 409.2 (400 MHz, DMSO-d₆) δ7.22 (t, J = 7.4 Hz, 3H), 7.17-7.02 (m, 3H), 6.67 (s, 1H), 6.60 (t, J =8.5 Hz, 1H), 4.49- 4.35 (m, 2H), 4.35 (t, J = 5.1 Hz, 1H), 3.42-3.39 (m,3H), 3.17 (t, J = 5.6 Hz, 1H), 2.60-2.52 (m, 2H), 2.51-2.46 (m, 1H),2.03 (tq, J = 14.9, 8.5, 6.9 Hz, 1H), 1.64-1.51 (m, 2H), 1.50-1.32 (m,11H), 1.05 (t, J = 6.2 Hz, 3H). B25

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (5-hydroxy-pentyl)phenyl]meth- oxy]pentan- 3-yl]carbamate 423.3 (400 MHz, CDCl₃) δ7.25 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 6.55 (s, 1H), 5.53(s, 1H), 4.91 (d, J = 9.6 Hz, 1H), 4.59 (d, J = 11.5 Hz, 1H), 4.38 (d, J= 11.5 Hz, 1H), 3.67-3.34 (m, 3H), 2.64 (t, J = 7.6 Hz, 2H), 2.32-2.25(m, 2H), 1.99 (dq, J = 15.7, 8.7, 8.2 Hz, 2H), 1.71-1.58 (m, 5H), 1.45(s, 12H), 1.21 (d, J = 6.2 Hz, 3H). B26

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (3-[2-[2-(2-hydroxyethoxy)eth- oxy]ethoxy]pro- pyl)phenyl]meth- oxy]pentan-3-yl]carbamate 527.4 (400 MHz, CDCl₃) δ 7.25 (d, J = 7.9 Hz, 2H), 7.19 (d,J = 7.9 Hz, 2H), 6.53 (s, 1H), 5.46 (s, 1H), 4.91 (d, J = 9.7 Hz, 1H),4.60 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.75 (dd, J = 5.4,3.6 Hz, 2H), 3.71-3.68 (m, 6H), 3.66-3.31 (m, 5H), 3.49 (t, J = 6.5 Hz,2H), 2.71 (t, J = 7.6 Hz, 2H), 2.29 (q, J = 6.3, 5.8 Hz, 2H), 2.09 (s,2H), 2.05-1.87 (m, 3H), 1.72 (d, J = 12.8 Hz, 1H), 1.46 (s, 9H), 1.22(d, J = 6.3 Hz, 3H). B27

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (1-hydroxy- 3,6,9,12-tetraoxapenta- decan-15- yl)phenyl]meth- oxy]pentan-3- yl]carbamate571.4 (400 MHz, CDCl₃) δ 7.25 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.9 Hz,2H), 6.52 (s, 1H), 5.48 (s, 1H), 4.91 (d, J = 9.6 Hz, 1H), 4.59 (d, J =11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.74 (t, J = 4.4 Hz, 2H), 3.69(s, 10H), 3.65-3.59 (m, 5H), 3.49 (t, J = 6.5 Hz, 2H), 2.70 (t, J = 7.6Hz, 2H), 2.35-2.21 (m, 3H), 2.05-1.87 (m, 3H), 1.75 (d, J = 5.6 Hz, 1H),1.46 (s, 9H), 1.22 (d, J = 6.2 Hz, 3H). B28

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (1-hydroxy- 3,6,9,12,15-pentaoxa- octadecan-18- yl)phenyl]meth- oxy]pentan-3- yl]carbamate 615.6(400 MHz, CDCl₃) δ 7.25 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H),6.49 (s, 1H), 5.49 (s, 1H), 4.91 (d, J = 9.7 Hz, 1H), 4.59 (d, J = 11.5Hz, 1H), 4.38 (d, J = 11.5 Hz, 1H), 3.79-3.56 (m, 22H), 3.48 (t, J = 6.5Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.36-2.23 (m, 2H), 2.02 (s, 2H), 1.91(dq, J = 8.8, 6.6 Hz, 2H), 1.77-1.64 (m, 1H), 1.45 (s, 9H), 1.21 (d, J =6.2 Hz, 3H). B29

tert-butyl N- [(3S,4R)- 1-carbamoyl-4- [[4-(3- hydroxy-propyl)phenyl]meth- oxy]pentan- 3-yl]carbamate 395.3 (400 MHz, DMSO-d₆)δ 7.25-7.21 (m, 3H), 7.15 (d, J = 7.8 Hz, 2H), 6.68 (s, 1H), 6.60 (d, J= 9.0 Hz, 1H), 4.47- 4.39 (m, 3H), 3.64-3.59 (m, 1H), 3.43-3.40 (m, 3H),2.59 (t, J = 7.8 Hz, 2H), 2.10-1.98 (m, 2H), 1.84-1.65 (m, 4H), 1.38 (s,9H), 1.06 (d, J = 5.9 Hz, 3H). B30

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4- [3-(2- hydroxyethoxy)pro-pyl]phenyl]meth- oxy)pentan-3- yl]carbamate 439.3 (400 MHz, CDCl₃) δ7.26 (s, 2H), 7.18 (d, J = 7.8 Hz, 2H), 4.91 (d, J = 9.7 Hz, 1H),4.59(d, J = 11.4 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.75-3.58 (m, 4H),3.56-3.49 (m, 3H), 2.71 (t, J = 7.6 Hz, 2H), 2.28 (q, J = 5.5, 4.5 Hz,2H), 1.96-1.90 (m, 2H), 1.89-1.85 (m, 4H), 1.71 (td, J = 12.2, 6.1 Hz,1H), 1.45 (s, 9H), 1.21 (d, J = 6.3 Hz, 3H). B31

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [3-[2-(2- hydroxyethoxy)eth-oxy]pro- pyl]phenyl)meth- oxy]pentan-3- yl]carbamate 483.3 (400 MHz,DMSO-d₆) δ 7.21 (d, J = 7.0 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.67 (s,1H), 6.64-6.56 (m, 1H), 4.56 (td, J = 5.4, 1.5 Hz, 1H), 4.51-4.38 (m,2H), 3.68-3.57 (m, 1H), 3.53 (dd, J = 5.6, 3.3 Hz, 2H), 3.51-3.45 (m,4H), 3.43 (dd, J = 6.2, 4.8 Hz, 3H), 3.39 (d, J = 6.4 Hz, 2H), 2.60 (t,J = 7.7 Hz, 2H), 2.14-.94 (m, 2H), 1.81- 1.74 (m, 3H), 1.50 (d, J = 17.4Hz, 2H), 1.37 (d, J = 9.6 Hz, 9H), 1.06 (d, J = 6.0 Hz, 3H). B33

3-[5-(4- hydroxybutyl)-3- methyl-2-oxo-1,3- benzodiazol-1-yl]piperidine-2,6- dione 332.2 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.03(d, J = 1.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.87 (dd, J = 8.1, 1.6Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.37 (t, J = 5.2 Hz, 1H), 3.41(q, J = 6.2 Hz, 2H), 3.34 (s, 1H), 2.98- 2.82 (m, 1H), 2.72 (td, J =12.9, 4.3 Hz, 1H), 2.67-2.58 (m, 3H), 2.00 (ddd, J = 11.2, 6.1, 3.9 Hz,1H), 1.62 (p, J = 7.6 Hz, 2H), 1.45 (p, J = 6.7 Hz, 2H). B34

3-[5-(6- hydroxyhexyl)-3- methyl-2-oxo-1,3- benzodiazol-1-yl]piperidine-2,6- dione 360.3 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.03(d, J = 1.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.1, 1.6Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.32 (s, 1H), 3.38 (q, J = 5.8Hz, 2H), 3.33 (s, 3H), 2.99-2.84 (m, 1H), 2.72 (td, J = 12.9, 4.4 Hz,1H), 2.66- 2.57 (m, 3H), 2.00 (ddd, J = 10.9, 5.8, 3.7 Hz, 1H), 1.59 (p,J = 7.7 Hz, 2H), 1.41 (q, J = 6.5 Hz, 2H), 1.36-1.25 (m, 4H). B35

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]propoxy]pentan-3-yl]carbamate 546.3 (400 MHz, CD₃OD) δ 7.40 (d, J = 1.9 Hz, 1H), 7.26(dd, J = 8.4, 1.9 Hz, 1H), 7.03-6.99 (m, 1H), 5.38-5.29 (m, 2H),3.59-3.48 (m, 1H), 3.48-3.45 (m, 1H), 3.43 (s, 3H), 2.97-2.89 (m, 1H),2.87-2.75 (m, 5H), 2.33-2.12 (m, 1H), 2.00 (s, 4H), 1.91 (q, J = 6.9 Hz,1H), 1.61 (s, 1H), 1.45 (s, 9H), 1.17-1.09 (m, 3H). B36

3-[5-(7- hydroxyheptyl)-3- methyl-2-oxo-1,3- benzodiazol-1-yl]piperidine-2,6- dione  374.20 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.02 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.1,1.6 Hz, 1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 4.31 (t, J = 5.2 Hz, 1H),3.38 (q, J = 6.3 Hz, 2H), 3.33 (s, 3H), 2.98- 2.83 (m, 1H), 2.75-2.69(m, 1H), 2.6- 2.55 (m, 3H), 2.05-1.94 (m, 1H), 1.60-1.58 (m, 2H),1.42-1.39 (m, 2H), 1.31-1.27 (m, 6H).

3-[3-Methyl-2-oxo-4-[(prop-2-yn-1-yloxy)methyl]-1,3-benzodiazol-1-yl]piperidine-2,6-dione(Intermediate B32)

Step 1.3-[4-(Hydroxymethyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione.To a solution of3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol) in dioxane (10.0 mL) were added Pd(PPh₃)₄ (171 mg, 0.15mmol) and (tributylstannyl)methanol (950 mg, 2.96 mmol) at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredfor 24 hours at 90° C. After cooling down to room temperature, thereaction was quenched with saturated aqueous KF solution (20.0 mL) andextracted with ethyl acetate (3×20.0 mL). The combined organic layerswere dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified byreversed phase flash chromatography with the following conditions:Column: Wel Flash™ C18-I, 20-40 um, 330 g; Eluent A: water (plus 10mmol/L FA); Eluent B: ACN; Gradient: 20%-40% B in 20 min; Flow rate: 80mL/min; Detector: UV 220/254 nm; desired fractions were collected at 30%B and concentrated under reduced pressure to afford the title compoundas white solid (200 mg, 47%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H),7.07 (dd, J=7.2, 1.9 Hz, 1H), 7.05-7.01 (m, 1H), 7.01-6.95 (m, 1H), 5.39(dd, J=12.7, 5.4 Hz, 1H), 4.75 (s, 2H), 3.62 (s, 3H), 2.91 (m, 1H), 2.74(m, 1H), 2.69-2.59 (m, 1H), 2.06-1.96 (m, 1H); MS (ESI, m/z):[(M+1)]⁺=290.25.

Step 2.3-[4-(Chloromethyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione.

To a solution of3-[4-(hydroxymethyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione(1.00 g, 3.46 mmol) in DCM (10.0 mL) were added DMF (5 mL) and SOCl₂(0.50 mL, 4.22 mmol) at 0° C. under nitrogen atmosphere. After stirringfor 2 hours at room temperature, the reaction was quenched by theaddition of water (20.0 mL) at 0° C. and extracted with DCM (3×30.0 mL).The combined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was concentrated under reduced pressure to afford the titlecompound as a white solid (1.00 g, 94%): ¹H NMR (400 MHz, DMSO-d₆) δ11.10 (s, 1H), 7.15-6.88 (m, 3H), 5.39 (dd, J=12.7, 5.4 Hz, 1H), 4.74(s, 2H), 3.62 (s, 3H), 2.91 (ddd, J=16.6, 13.4, 5.2 Hz, 1H), 2.80-2.58(m, 2H), 2.07-1.91 (m, 1H); MS (ESI, m/z): [(M+1)]⁺=308.07.

Step 3.3-[3-Methyl-2-oxo-4-[(prop-2-yn-1-yloxy)methyl]-1,3-benzodiazol-1-yl]piperidine-2,6-dione(Intermediate B32). To a mixture of3-[4-(chloromethyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione(1.50 g, 4.87 mmol) and Ag₂CO₃ (4.03 g, 14.6 mmol) in ACN (15.0 mL)/DMA(5.00 mL) was added propargyl alcohol (1.37 g, 24.4 mmol) at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredfor 16 hours at 75° C. After cooling down to room temperature, themixture was filtered. The filtered cake was washed with DCM (3×10.0 mL).The combined filtrates were concentrated under reduced pressure. Theresidue was purified by reversed phase flash chromatography with thefollowing conditions: Column: WelFlash™ C18-I, 20-40 um, 330 g; EluentA: water (plus 10 mmol/L NH₄HCO₃); Eluent B: ACN; Gradient: 25%-45% B in20 min; Flow rate: 80 mL/min; Detector: UV 220/254 nm; desired fractionswere collected at 38% B and concentrated under reduced pressure toafford the title compound as a light yellow solid (450 mg, 29%): ¹H NMR(400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 7.15 (p, J=4.0 Hz, 1H), 7.02 (d,J=4.5 Hz, 2H), 5.40 (dd, J=12.7, 5.4 Hz, 1H), 4.77 (s, 2H), 4.22 (d,J=2.4 Hz, 2H), 3.58 (s, 3H), 3.53 (t, J=2.4 Hz, 1H), 2.90 (m, 1H),2.78-2.59 (m, 2H), 2.03 (m, 1H); MS (ESI, m/z): [(M+1)]⁺=328.10.

Tert-butylN-[3-[4-([[(2R,3S)-3-amino-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]propyl]carbamate(Intermediate C)

Step 1. (4S,5R)-4-Amino-5-[(4-bromophenyl)methoxy]hexanamidehydrochloride. To a solution of tert-butylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(4.50 g, 10.8 mmol) in 1,4-dioxane (50.0 mL) was added a HCl solution (4M in 1,4-dioxane, 16.0 mL) at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 1 hour at room temperature. Theresulting mixture was concentrated under reduced pressure to afford thetitle compound as a white solid (2.60 g, 65%): ¹H NMR (400 MHz, D2O) δ7.54-7.46 (m, 2H), 7.22 (d, J=8.2 Hz, 2H), 4.52 (d, J=11.9 Hz, 1H), 4.43(d, J=11.9 Hz, 1H), 3.77 (dd, J=6.5, 3.6 Hz, 1H), 3.37-3.30 (m, 1H),2.29 (t, J=7.6 Hz, 2H), 1.81 (dh, J=22.4, 7.2 Hz, 2H), 1.12 (d, J=6.6Hz, 3H); MS (ESI, m/z): [(M+1)]⁺=315.10, 317.10.

Step 2. 2-(Trimethylsilyl)ethylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate.To a stirred solution of(4S,5R)-4-amino-5-[(4-bromophenyl)methoxy]hexanamide hydrochloride (3.40g, 9.67 mmol) in water (35.0 mL) was added a solution of TEA (2.93 g,29.0 mmol) in 1,4-dioxane (35.0 mL) followed by the addition of2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (2.76 g, 10.7mmol) at room temperature. The resulting mixture was stirred for 16hours at room temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by reversed phase flash chromatography with the followingconditions: column, C18 silica gel; 20-40 μm, 330 g; Eluent A: water(plus 10 mmol/L AcOH); Eluent B: ACN; Gradient: 60%-80% B in 20 min;Flow rate: 80 mL/min; Detector: UV 220/254 nm; desired fractions werecollected at 65% and concentrated under reduced pressure to afford thetitle compound as a colorless solid (3.50 g, 79%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.56-7.47 (m, 2H), 7.36-7.16 (m, 3H), 6.87 (d, J=9.3 Hz, 1H),6.70 (s, 1H), 4.53-4.41 (m, 2H), 4.11-3.94 (m, 2H), 3.57-3.39 (m, 2H),2.18-1.96 (m, 2H), 1.85-1.72 (m, 1H), 1.58-1.40 (m, 1H), 1.07 (d, J=6.1Hz, 3H), 0.92 (t, J=8.4 Hz, 2H), 0.02 (s, 9H); MS (ESI, m/z):[(M+1)]⁺=459.10, 461.10.

Step 3. Tert-butylN-[3-[4-([[(2R,3S)-5-carbamoyl-3-([[2-(trimethylsilyl)ethoxy]carbonyl]amino)pentan-2-yl]oxy]methyl)phenyl]prop-2-yn-1-yl]carbamate.To a solution of 2-(trimethylsilyl)ethylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(2.18 g, 4.75 mmol) in DMSO (30 mL) were added tert-butylN-(prop-2-yn-1-yl)carbamate (3.68 g, 23.7 mmol), TEA (15 mL), CuI (90.4mg, 0.48 mmol) and Pd(PPh₃)₄ (548 mg, 0.48 mmol) at room temperatureunder nitrogen atmosphere. The reaction mixture was purged with nitrogenfor 3 times and was stirred for 16 hours at 90° C. under nitrogenatmosphere. The resulting mixture cooled down to room temperature andconcentrated under reduced pressure. The residue was purified byreversed phase flash chromatography with the following conditions:column, C18 silica gel; 20-40 m, 330 g; Eluent A: water (plus 10 mmol/LTEA); Eluent B: ACN; Gradient: 55%-75% B in 20 min; Flow rate: 80mL/min; Detector: UV 220/254 nm; desired fractions were collected at 65%and concentrated under reduced pressure to afford the title compound asa brown solid (2.30 g, 91%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.37-7.31 (m,4H), 7.21 (s, 1H), 6.87 (d, J=9.2 Hz, 1H), 6.69 (s, 1H), 4.49 (d, J=2.1Hz, 2H), 4.12-3.88 (m, 4H), 3.56-3.38 (m, 2H), 2.15-1.97 (m, 2H), 1.78(dd, J=10.0, 3.7 Hz, 1H), 1.47 (s, 1H), 1.40 (s, 10H), 1.07 (d, J=6.2Hz, 3H), 0.92 (t, J=8.4 Hz, 2H), 0.00 (s, 9H); MS (ESI, m/z):[(M+1)]⁺=534.30.

The intermediates in Table 17 were prepared according to step 3 of theprocedure to prepare Intermediate C.

TABLE 17 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR C-3-1

tert-butyl ((2R,3S)-6- amino-2-((4-(3- (((benzyloxy)car-bonyl)amino)prop- 1-yn-1- yl)benzyl)oxy)-6- oxohexan-3- yl)carbamate524.30 (400 MHz, DMSO-d₆) δ 7.44-7.29 (m, 10H), 7.23 (s, br, 1H), 6.69(s, 1H), 6.65-6.30 (m, 1H), 5.07 (s, 2H), 4.57-4.38 (m, 2H), 4.07 (d, J= 5.6 Hz, 1H), 3.47-3.41 (m, 3H), 2.09-2.05 (m, 2H), 1.79- 1.75 (m, 1H),1.52-1.48 (m, 1H), 1.39 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H).

Step 4. Tert-butylN-[3-[4-([[(2R,3S)-5-carbamoyl-3-([[2-(trimethylsilyl)ethoxy]carbonyl]amino)pentan-2-yl]oxy]methyl)phenyl]propyl]carbamate.To a solution of tert-butylN-[3-[4-([[(2R,3S)-5-carbamoyl-3-([[2-(trimethylsilyl)ethoxy]carbonyl]amino)pentan-2-yl]oxy]methyl)phenyl]prop-2-yn-1-yl]carbamate(330 mg, 0.62 mmol) in THF (20.0 mL) was added Pd—C (100 mg, 10%palladium on activated carbon) at room temperature under nitrogenatmosphere. The resulting mixture was purged with H₂ for 3 times andstirred for 2 hours at room temperature under hydrogen atmosphere. Thereaction mixture was filtered through a Celite pad. The filtrate wasconcentrated under reduced pressure to afford the title compound as abrown solid (300 mg, 90%): ¹H NMR (400 MHz, DMSO-d) δ 7.24-7.22 (m, 3H),7.14 (d, J=7.8 Hz, 2H), 6.84 (d, J=8.7 Hz, 1H), 6.66 (d, J=14.7 Hz, 1H),4.50-4.38 (m, 2H), 4.11-3.95 (m, 2H), 3.49 (d, J=8.7 Hz, 1H), 3.41 (t,J=6.0 Hz, 1H), 2.92 (q, J=6.6 Hz, 2H), 2.55 (d, J=7.7 Hz, 2H), 2.13-1.97(m, 2H), 1.79 (dt, J=11.8, 4.4 Hz, 1H), 1.65 (p, J=7.3 Hz, 2H),1.57-1.41 (m, 2H), 1.38 (s, 9H), 1.06 (d, J=6.1 Hz, 3H), 0.92 (t, J=8.4Hz, 2H), 0.00 (s, 9H); MS (ESI, m/z): [(M+1)]⁺=538.45.

The intermediates in Table 18 were prepared according to step 4 of theprocedure to prepare Intermediate C.

TABLE 18 Characterization data for intermediates prepared according toabove. MS: Intermediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMR C-4-1

tert-butyl N- [(3S,4R)-4-[[4- (3-amino- propyl)phenyl]meth- oxy]-1-carbamoyl- pentan-3- yl]carbamate 394.30 ¹H NMR (400 MHz, DMSO-d₆) δ7.26-7.19 (m, 3H), 7.14 (d, J = 7.8 Hz, 2H), 6.68 (s, 1H), 6.61 (d, J =9.1 Hz, 1H), 4.49- 4.37 (m, 2H), 3.53-3.38 (m, 2H), 3.18 (s, 2H),2.62-2.51 (m, 4H), 2.12-1.95 (m, 2H), 1.88- 1.74 (m, 1H), 1.64-1.60 (m,2H), 1.53-1.43 (m, 1H), 1.39 (s, 9H), 1.06 (s, 3H) C-4-2

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (piperidin-4-yl-methyl)phenyl]meth- oxy]pentan- 3-yl]carbamate 434.30 ¹H NMR (400 MHz,DMSO-d₆) δ 7.27-7.17 (m, 3H), 7.10 (d, J = 7.8 Hz, 2H), 6.69 (s, 1H),6.62 (d, J = 9.1 Hz, 1H), 4.53-4.36 (m, 2H), 3.52-3.19 (m, 4H),2.95-2.79 (m, 2H), 2.45 (d, J = 6.9 Hz, 2H), 2.40-2.31 (m, 2H),2.08-2.01 (m, 2H), 1.81-1.77 (m, 1H), 1.58-1.40 (m, 3H), 1.39 (s, 9H),1.09-0.95 (m, 5H).

Step 5. Tert-butyl N-[3-[4-([[(2R,3S)-3-amino-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]propyl]carbamate(Intermediate C). A solution of tert-butylN-[13-[14-([[(2R,3S)-5-carbamoyl-3-([[2-(trimethylsilyl) ethoxy]carbonyl] amino)pentan-2-yl]oxy]methyl)phenyl]propyl]carbamate (200 mg,0.37 mmol) and TBAF (292 mg, 1.12 mmol) in THF (10.0 mL) was stirred for16 hours at room temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by reversed phase flash chromatography with the followingconditions: column, C18 silica gel; 20-40 μm, 40 g; Mobile phase A:water (plus 10 mmol/L AcOH); Mobile phase B: CAN. Gradient: 15% to 35% Bin 20 min; Detector: UV 254/220 nm; desired fractions were collected at27% B and concentrated under reduced pressure to afford the titlecompound as a white solid (130 mg, 890%): ¹H NMR (400 MHz, DMSO-d₆) δ7.23 (d, J=7.9 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 4.47 (d, J=11.7 Hz, 1H),4.38 (d, J=11.7 Hz, 1H), 3.32 (dd, J=6.4, 4.7 Hz, 1H), 2.92 (q, J=6.7Hz, 2H), 2.71-2.61 (m, 1H), 2.55 (d, J=7.6 Hz, 2H), 2.26-2.00 (m, 2H),1.65 (s, 8H), 1.38 (s, 9H), 1.08 (dd, J=9.8, 6.1 Hz, 3H); MS (ESI, m/z):[(M+1)]⁺=394.30.

(9H-fluoren-9-yl)methylN-[(2S)-1-[(1R,2S,5S)-2-[[(3S,4R)-4-[[4-(3-aminopropyl)phenyl]methoxyl-1-carbamoylpentan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-1-oxohexan-2-yl]carbamatehydrochloride (Intermediate D)

Step 1. 9H-fluoren-9-ylmethyl(1R,2S,5S)-2-[[(3S,4R)-4-[(4-[3-[(tert-butoxycarbonyl)amino]propyl]phenyl)methoxyl-1-carbamoylpentan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate.To a solution of(1R,2S,5S)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylicacid (390 mg, 1.12 mmol) and tert-butylN-[3-[4-([[(2R,3S)-3-amino-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]propyl]carbamate(439 mg, 1.12 mmol) in DMA (10 mL) was added TEA (339 mg, 3.35 mmol).The mixture was stirred at room temperature for 5 min then HATU (552 mg,1.45 mmol) was added. The mixture was stirred at room temperature for 1hour. The resulting mixture was purified by reversed phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 330 g; Eluent A: water (plus 10 mmol/L HOAc); Eluent B: ACN;Gradient: 40%-60% B in 20 min; Flow rate: 80 mL/min; Detector: UV220/254 nm; desired fractions were collected at 58% B and concentratedunder reduced pressure to afford the title compound (610 mg, 76%) as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (d, J=8.0 Hz, 2H), 7.64(q, J=7.0, 6.6 Hz, 2H), 7.43 (t, J=7.4 Hz, 2H), 7.39-7.28 (m, 2H),7.26-7.04 (m, 5H), 6.86 (s, 1H), 6.73-6.58 (m, 1H), 4.50-4.38 (m, 2H),4.33-4.08 (m, 3H), 3.78 (d, J=39.1 Hz, 1H), 3.40 (t, J=6.0 Hz, 2H),2.94-2.86 (m, 2H), 2.55 (d, J=8.0 Hz, 2H), 2.09-1.93 (m, 2H), 1.82 (s,2H), 1.66-1.62 (m, 4H), 1.38 (s, 10H), 1.13-1.06 (m, 3H), 0.69 (s, 1H),0.55 (s, 1H); MS (ESI, m/z): [(M+1)]⁺=725.35.

Step 2. Tert-butylN-[3-[4-([[(2R,3S)-3-[[(1R,2S,5S)-3-azabicyclo[3.1.0]hexan-2-yl]formamido]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]propyl]carbamate.To a solution of (9H-fluoren-9-yl)methyl(1R,2S,5S)-2-[[(3S,4R)-4-[[4-(3-[[(tert-butoxy)carbonyl]amino]propyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(610 mg, 0.84 mmol) in DMF (10 mL) was added diethylamine (2 mL) at roomtemperature. The mixture was stirred at room temperature for 20 min. Theresulting mixture was acidified to pH=6 with HOAc (4 mL) at 0° C. andpurified by reversed phase flash chromatography with the followingconditions: Column: WelFlash™ C18-I, 20-40 um, 120 g; Eluent A: water(plus 10 mmol/L HOAc); Eluent B: ACN; Gradient: 15%-35% B in 20 min;Flow rate: 80 mL/min; Detector: UV 220/254 nm; desired fractions werecollected at 26% B and concentrated under reduced pressure to afford thetitle compound as a white solid (400 mg, 95%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.70 (d, J=9.4 Hz, 1H), 7.28-7.20 (m, 3H), 7.18-7.13 (m, 2H), 6.85 (d,J=6.2 Hz, 1H), 6.69 (s, 1H), 4.50-4.38 (m, 2H), 3.83-3.73 (m, 1H), 3.56(d, J=3.9 Hz, 1H), 3.44 (p, J=6.1 Hz, 1H), 2.94-2.90 (m, 3H), 2.81 (dd,J=10.7, 3.6 Hz, 1H), 2.55 (d, J=7.6 Hz, 2H), 2.08-1.97 (m, 2H), 1.87(dtd, J=17.2, 7.1, 3.8 Hz, 1H), 1.66 (q, J=7.3 Hz, 2H), 1.61-1.49 (m,2H), 1.38 (s, 11H), 1.09 (d, J=6.3 Hz, 3H), 0.32 (q, J=4.3 Hz, 1H), 0.25(td, J=7.7, 4.7 Hz, 1H); MS (ESI, m/z): [(M+1)]⁺=503.40.

Step 3. (9H-fluoren-9-yl)methylN-[(2S)-1-[(1R,2S,5S)-2-[[(3S,4R)-4-[[4-(3-[[(tert-butoxy)carbonyl]amino]propyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-1-oxohexan-2-yl]carbamate.To a solution of tert-butylN-[3-[4-([[(2R,3S)-3-[[(1R,2S,5S)-3-azabicyclo[3.1.0]hexan-2-yl]formamido]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]propyl]carbamate(400 mg, 0.80 mmol) and(2S)-2-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)hexanoic acid (281 mg,0.80 mmol) in DMA (8 mL) was added TEA (242 mg, 2.39 mmol). The mixturewas stirred at room temperature for 5 min then HATU (393 mg, 1.04 mmol)was added. The mixture was stirred at room temperature for 1 hour. Theresulting mixture was purified by reversed phase flash chromatographywith the following conditions: Column: WelFlash™ C18-I, 20-40 um, 330 g;Eluent A: water (plus 10 mmol/L HOAc); Eluent B: ACN; Gradient: 40%-60%B in 20 min; Flow rate: 80 mL/min; Detector: UV 220/254 nm; desiredfractions were collected at 58% B and concentrated under reducedpressure to afford the title compound as a white solid (600 mg, 90%): ¹HNMR (400 MHz, DMSO-d₄) δ 7.90 (d, J=7.5 Hz, 2H), 7.74 (dd, J=7.5, 3.9Hz, 2H), 7.60 (dd, J=12.4, 8.3 Hz, 2H), 7.43 (t, J=7.5 Hz, 2H), 7.34 (t,J=7.4 Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 7.06 (s,1H), 6.86 (s, 1H), 6.68 (s, 1H), 4.53-4.32 (m, 3H), 4.29-4.19 (m, 3H),4.11 (d, J=6.3 Hz, 1H), 3.88 (d, J=9.9 Hz, 1H), 3.72 (s, 1H), 3.60 (d,J=9.7 Hz, 1H), 3.38 (t, J=6.2 Hz, 1H), 2.94-2.88 (m, 2H), 2.70 (s, 1H),2.55 (d, J=7.8 Hz, 2H), 2.11 (d, J=9.2 Hz, 2H), 1.81 (s, 1H), 1.69 (s,1H), 1.65 (t, J=7.4 Hz, 2H), 1.55-1.52 (m, 3H), 1.39 (s, 9H), 1.31-1.26(m, 3H), 1.10-1.07 (m, 3H), 0.89-0.86 (m, 3H), 0.71 (d, J=4.5 Hz, 1H),0.57 (s, 1H); MS (ESI, m/z): [(M+1)]⁺=838.35.

Step 4. (9H-fluoren-9-yl)methylN-[(2S)-1-[(1R,2S,5S)-2-[[(3S,4R)-4-[[4-(3-aminopropyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-1-oxohexan-2-yl]carbamatehydrochloride (Intermediate D). To a solution of (9H-fluoren-9-yl)methylN-[(2S)-1-[(1R,2S,5S)-2-[[(3S,4R)-4-[[4-(3-[[(tert-butoxy)carbonyl]amino]propyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-1-oxohexan-2-yl]carbamate(600 mg, 0.72 mmol) in dioxane (6 mL) was added 4 M HCl (gas) in1,4-dioxane (6 mL) at room temperature. The reaction mixture was stirredat room temperature for 1 hour. The resulting mixture was concentratedunder reduced pressure to give the title compound as a white solid (550mg, 99%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.91-7.89 (m, 4H), 7.73 (dd,J=7.3, 3.9 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.42 (t, J=7.5 Hz, 2H), 7.33(t, J=7.3 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H), 7.08(s, 1H), 6.69 (s, 1H), 4.50-4.36 (m, 3H), 4.28-4.18 (m, 3H), 4.14-4.05(m, 1H), 3.91-3.83 (m, 1H), 3.71 (s, 1H), 2.79 (s, 5H), 2.64 (t, J=7.7Hz, 2H), 2.11 (d, J=8.2 Hz, 2H), 1.85-1.80 (m, 3H), 1.71 (s, 1H),1.52-1.47 (m, 3H), 1.36-1.19 (m, 5H), 1.09 (d, J=6.2 Hz, 3H), 0.88-0.85(m, 3H), 0.72-0.70 (m, 1H), 0.60-0.53 (m, 1H); MS (ESI, m/z):[(M+1)]⁺=738.35.

(9H-fluoren-9-yl)methylN-[(2S,11S)-2-[[(3S,4R)-4-[[4-(3-aminopropyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (Intermediate E)

Step 1. (9H-fluoren-9-yl)methylN-[(2S,11S)-2-[[(3S,4R)-4-[[4-(3-[[(tert-butoxy)carbonyl]amino]propyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate. To a solutionof(2S,11S)-11-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-triene-2-carboxylic acid (850 mg, 1.81mmol) in DMA (15 mL) were added TEA (551 mg, 5.44 mmol) and HATU (897mg, 2.36 mmol) at room temperature. The mixture was stirred at roomtemperature for 10 min. Then tert-butylN-[3-[4-([[(2R,3S)-3-amino-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]propyl]carbamate(714 mg, 1.81 mmol) was added. The mixture was stirred at roomtemperature for 1 hour. The resulting mixture was diluted with water (50mL). The precipitated solids were collected by filtration and washedwith water (3×30 mL), dried under vacuum to give the title compound as awhite solid (1.40 g, 91%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J=7.5Hz, 2H), 7.84 (d, J=9.2 Hz, 1H), 7.75 (q, J=8.3, 7.6 Hz, 3H), 7.43 (t,J=7.6 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H), 7.17 (d, J=7.8 Hz, 3H), 7.11 (d,J=7.8 Hz, 2H), 7.06 (d, J=7.6 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 6.85 (s,1H), 6.69 (s, 1H), 5.06 (d, J=10.2 Hz, 1H), 4.40 (s, 2H), 4.34-4.21 (m,3H), 4.13 (s, 1H), 3.79 (s, 1H), 3.46-3.40 (m, 2H), 3.17 (d, J=16.8 Hz,1H), 3.08 (d, J=14.4 Hz, 1H), 2.96-2.91 (m, 2H), 2.85 (d, J=16.7 Hz,1H), 2.55 (d, J=7.6 Hz, 2H), 2.11-2.02 (m, 3H), 1.78 (s, 1H), 1.67 (q,J=7.3 Hz, 2H), 1.57 (s, 1H), 1.39 (s, 9H), 1.08 (d, J=6.2 Hz, 3H), 0.94(t, J=7.3 Hz, 1H); MS (ESI, m/z): [(M+1)]⁺=844.50.

The intermediates in Table 19 were prepared according to step 1 of theprocedure to prepare Intermediate E.

TABLE 19 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRE-1-1

tert-butyl N-(7- [[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]car- bamoyl)pyr- rolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]car- bamoyl]hep- tyl)carbamate 672.45(400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.84 (d, J= 9.3 Hz, 1H), 7.41 (q, J = 8.5 Hz, 4H), 6.74 (d, J = 6.1 Hz, 1H), 4.55(d, J = 9.4 Hz, 1H), 4.44 (q, J = 7.7 Hz, 2H), 4.36 (s, 1H), 4.24-4.20(m, 1H), 3.65 (t, J = 8.7 Hz, 1H), 3.31 (s, 2H), 2.88 (q, J = 6.7 Hz,2H), 2.45 (s, 3H), 2.28-2.24 (m, 1H), 2.16-2.05 (m, 1H), 2.04-2.00 (m,1H), 1.93-1.89 (m, 1H), 1.55-1.42 (m, 2H), 1.37 (s, 9H), 1.25-1.20 (m,8H), 0.94 (s, 9H) E-1-2

tert-butyl N-(8- [[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]carbamoyl)pyr- rolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]car- bamoyl]octyl)car- bamate 686.30 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.84 (d, J = 9.3Hz, 1H), 7.41 (q, J = 8.4 Hz, 4H), 6.75 (t, J = 5.5 Hz, 1H), 5.13 (s,1H), 4.55 (d, J = 9.4 Hz, 1H), 4.51-4.39 (m, 2H), 4.36 (s, 1H), 4.22(dd, J = 15.9, 5.5 Hz, 1H), 3.72-3.60 (m, 2H), 2.88 (q, J = 6.6 Hz, 2H),2.45 (s, 3H), 2.29-2.23 (m, 1H), 2.17-2.04 (m, 1H), 2.05-2.01 (m, 1H),1.94-1.89 (m, 1H), 1.49-1.45 (m, 2H), 1.37 (s, 9H), 1.37-1.33 (m, 2H),1.25- 1.18 (m, 8H), 0.94 (s, 9H) E-1-3

tert-butyl N-(9- [[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]carbamoyl)pyr- rolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]no- nyl)carbamate 700.60 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.84 (d, J = 9.3Hz, 1H), 7.41 (q, J = 8.3 Hz, 4H), 6.75 (t, J = 5.8 Hz, 1H), 5.13 (s,1H), 4.55 (d J = 9.4 Hz, 1H), 4.51-4.39 (m, 2H), 4.36 (s, 1H), 4.24-4.20(m, 1H), 3.72- 3.61 (m, 2H), 3.18 (s, 1H), 2.97-2.84 (m, 2H), 2.45 (s,3H), 2.32-2.20 (m, 1H), 2.15 -1.99 (m, 2H), 1.93-1.89 (m, 1H), 1.52-1.48(m, 1H), 1.37 (s, 9H), 1.25-1.21 (m, 12H), 0.94 (s, 9H) E-1-4

tert-butyl N- [(1S)-1-[[(3- bromo- phenyl)meth- yl]carbamoyl]-3-carbamoylpro- pyl]carbamate 413.95, 415.95 (400 MHz, CDCl₃) δ 7.46-.40(m, 2H), 7.24-7.21 (m, 2H), 7.12 (s, 1H), 6.06 (s, 1H), 5.71 (s, 1H),5.49 (s, 1H), 4.44 (d, J = 5.6 Hz, 2H), 4.20 (s, 1H), 2.53-2.42 (m, 1H),2.40-2.31 (m, 1H), 2.21-2.08 (m, 1H), 2.06-1.96 (m, 1H), 1.45 (s, 9H)

Step 2. (9H-fluoren-9-yl)methylN-[(2S,11S)-2-[[(3SAR)-4-[[4-(3-aminopropyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (IntermediateE). To a solution of (9H-fluoren-9-yl)methylN-[(2S,11S)-2-[[(3S,4R)-4-[[4-(3-[[(tert-butoxy) carbonyl] amino]propyl)phenyl] methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (1.40 g, 1.66 mmol)in dioxane (15 mL) was added a solution of 4 M HCl (gas) in 1,4-dioxane(15 mL) at room temperature. The mixture was stirred at room temperaturefor 1 hour. The resulting mixture was concentrated under reducedpressure to give the title compound as a white solid (1.20 g, 97R): 1HNMR (400 MHz, DMSO₆) δ 7.94-7.83 (s, 3H), 7.76 (t, J=7.1 Hz, 2H), 7.43(t, J=7.5 Hz, 2H), 7.38-7.31 (8, 2H), 7.25-7.09 (d, 5H), 7.09-6.94 (m,3H), 6.71 (s, 1H), 5.06 (d, J=10.8 Hz, 1H), 4.41 (s, 2H), 4.33-4.22 (9,2H), 4.13 (s, 1H), 3.78 (s, 1H), 3.45 (dd, J=11.6, 6.0 Hz, 2H),3.35-3.30 (m, 3H), 3.20-3.13 (m, 2H), 3.05 (s, 1H), 2.85 (d, J=16.7 Hz,1H), 2.72 (d, J=7.4 Hz, 1H), 2.60 (d, J=7.7 Hz, 1H), 2.09-2.06 (d, 3H),1.87-1.71 (m, 3H), 1.57 (s, 2H), 1.31 (p, J=7.1 Hz, 2H), 1.08 (d, J=6.2Hz, 3H); MS (ESI, m/z): [)M+1)]⁺=744.35.

The intermediates in Table 20 were prepared according to step 2 of theprocedure to prepare Intermediate E.

TABLE 20 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS :[(M + 1)]⁺ ¹H-NMR E1

(2S,4R)-1-[(2S)- 2-(8-amino- octanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N- [[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 572.50 (400 MHz, DMSO-d₆) δ9.13 (s, 1H), 8.61 (d, J = 6.4 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.42(q, J = 8.3 Hz, 4H), 5.76 (s, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.48-4.39(m, 2H), 4.35 (s, 1H), 4.23 (dd, J = 15.9, 5.2 Hz, 1H), 3.71--3.63 (m,2H), 2.74 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.28-2.24 (m, 1H),2.19-2.00 (m, 2H), 1.92-1.89 (m, 1H), 1.82-1.70 (m, 2H), 1.60-1.42 (m,2H), 1.28-1.24 (m, 8H), 0.94 (s, 9H) E2

(2S,4R)-1-[(2S)- 2-(9- aminononan- amido)-3,3- dimethylbutanoyl]-4-hydroxy-N- [[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 586.50 (400 MHz, DMSO-d₆) δ9.30-9.09 (m, 1H), 8.63 (t, J = 5.7 Hz, 1H), 7.85 (d, J = 9.4 Hz, 1H),7.44-7.40 (m, 4H), 5.26 (d, J = 13.9 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H),4.48-4.38 (m, 2H), 4.35 (d, J = 4.1 Hz, 1H), 4.25- 4.21 (m, 1H),3.71-3.63 (m, 2H), 2.73 (q, J = 7.5, 7.0 Hz, 2H), 2.47 (s, 3H),2.30-2.24 (m, 1H), 2.18-2.00 (m, 2H), 1.93-1.88 (m, 1H), 1.61-1.57 (m,4H), 1.20-1.16 (m, 10H), 0.94 (s, 9H) E3

(2S,4R)-1-[(2S)- 2-(10- aminodecan- amido)-3,3- dimethylbutanoyl]-4-hydroxy-N- [[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]methyl]pyr-rolidine-2- carboxamide hydrochloride 600.50 (400 MHz, DMSO-d₆) δ 9.07(s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J = 9.3 Hz,1H), 7.46- 7.36 (m, 4H), 4.55 (d, J = 9.3 Hz, 1H), 4.49-4.39 (m, 2H),4.36 (s, 1H), 4.24-4.20 (m, 1H), 3.71-3.63 (m, 2H), 2.76-2.72 (m, 2H),2.46 (d, J = 3.7 Hz, 3H), 2.27-2.23 (m, 1H), 2.17-2.01 (m, 2H),1.93-1.88 (m, 1H), 1.55-1.48 (m, 4H), 1.27-1.23 (m, 12H), 0.94 (s, 9H)E4

(4S,5R)-4- Amino-5- (benzyloxy)hex- anamide hydrochloride 237.25 (400MHz, DMSO-d₆) δ 8.29-8.10 (m, 2H), 7.50 (s, 1H), 7.42-7.25 (m, 6H), 6.92(s, 1H), 4.47 (s, 2H), 3.86- 3.75 (m, 1H), 3.33-3.12 (m, 1H), 2.27 (t, J= 8.0 Hz, 2H), 1.77 (p, J = 7.5 Hz, 2H), 1.16 (d, J = 6.4 Hz, 3H) E5

1-Methyl-6- (piperazin-1-yl)- 3H-1,3- benzodiazol-2- one 233.10 (400MHz, DMSO-d₆) δ 10.54 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H),6.57 (d, J = 8.5 Hz, 1H), 3.24 (s, 3H), 3.04-2.97 (m, 4H), 2.94-2.86 (m,4H), 1.42-1.37 (m, 1H) E6

3-[3-Methyl-2- oxo-5-(piperidin- 4-ylmethyl)-1,3- benzodiazol-1-yl]piperidine-2,6- dione trifluoroacetate 357.15 (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.61 (d, J = 11.3 Hz, 1H), 7.04 (d, J = 7.4 Hz, 2H), 6.86(d, J = 8.0 Hz, 1H), 5.35 (dd, J = 12.7, 5.4 Hz, 1H), 3.47-3.42 (s, 1H),3.33 (s, 3H), 3.25 (d, J = 12.5 Hz, 2H), 2.99-2.54 (m, 6H), 2.04-1.96(m, 1H), 1.84-1.67 (m, 3H), 1.42-1.26 (m, 2H) E7

3-[3-Methyl-2- oxo-5-(piperidin- 4-yl)-1,3- benzodiazol-1-yl]piperidine-2,6- dione trifluoroacetate 343.15 (400 MHz, DMSO-d₆) δ11.10 (s, 1H), 8.75 (d, J = 11.5 Hz, 1H), 8.46 (d, J = 11.7 Hz, 1H),7.13-7.02 (m, 2H), 6.91 (dd, J = 8.2, 1.6 Hz, 1H), 5.36 (dd, J = 12.7,5.4 Hz, 1H), 3.35 (s, 3H), 3.11-2.84 (m, 4H), 2.78-2.58 (m, 2H),2.09-1.75 (m, 5H) E8

(2R)-2-amino-N- (diphenyl- methyl)pentane- diamide hydrochloride 312.10(400 MHz, DMSO-d₆) δ 9.62 (d, J = 8.9 Hz, 1H), 8.40 (s, 3H), 7.52 (s,1H), 7.41-7.28 (m, 8H), 7.31-7.22 (m, 2H), 6.96 (s, 1H), 6.15 (d, J =8.4 Hz, 1H), 4.02 (d, J = 9.5 Hz, 1H), 2.21 (dd, J = 9.2, 6.4 Hz, 2H),2.04-1.94 (m, 2H) E9

(2S)-2-amino-N- [(4-isopropyl- phenyl)meth- yl]pentanedi- amidehydrochloride 278.20 (400 MHz, DMSO-d₆) δ 8.99 (d, J = 5.3 Hz, 1H),8.35-8.27 (s, 2H), 7.49 (s, 1H), 7.24-7.20 (m, 4H), 6.95 (s, 1H), 4.30(t, J = 5.8 Hz, 2H), 3.81 (d, J = 5.9 Hz, 1H), 2.92-2.84 (m, 1H), 2.20(m, 2H), 1.98-1.94 (m, 2H), 1.19 (d, J = 6.9 Hz, 6H) E10

(2S)-2-amino-N-[(4- methanesulfonyl- phenyl)meth- yl]pentanediamidehydrochloride 314.05 (300 MHz, DMSO-d₆) δ 9.40 (t, J = 5.8 Hz, 1H), 8.48(br, 3H), 7.96-7.83 (m, 2H), 7.74-7.53 (m, 2H), 7.13 (d, J = 100.0 Hz,3H), 4.56-4.27 (m, 2H), 4.02-3.81 (m, 1H), 3.22 (s, 3H), 2.24 (t, J =8.0 Hz, 2H), 2.02 (q, J = 8.3, 7.7 Hz, 2H)

Tert-butylN-[(3S,4R)-1-carbamoyl-4-[[4-(5-[13-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]pentyl)phenyl]methoxy]pentan-3-yl]carbamate(Intermediate F)

Step 1.3-(5-[3-[(5-Bromopentyl)oxy]propyl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione.To a solution of3-(5-[3-[(5-hydroxypentyl)oxy]propyl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione(760 mg, 1.88 mmol) in THF (20.0 mL) were added PPh₃ (988 mg, 3.77 mmol)and CBr₄ (1.25 g, 3.77 mmol) at 0° C. The mixture was stirred at 25° C.for 16 hours. The mixture was purified by reverse phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 330 g; Eluent A: water (plus 10 mmol/L HOAc); Eluent B: ACN;Gradient: 40%-60% B in 20 min; Flow rate: 50 mL/min; Detector: UV220/254 nm; desired fractions were collected at 53% B and concentratedunder reduced pressure to afford the title compound as a green oil (780mg, 89%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.08-6.96 (m, 2H),6.87 (dd, J=8.1, 1.6 Hz, 1H), 5.34 (dd, J=12.7, 5.4 Hz, 1H), 3.55 (t,J=6.7 Hz, 2H), 3.42-3.33 (m, 7H), 2.90 (ddd, J=16.5, 13.0, 5.2 Hz, 1H),2.79-2.58 (m, 4H), 2.05-1.95 (m, 1H), 1.83-1.80 (m, 4H), 1.60-1.40 (m,4H); MS (ESI, m/z): [(M+1)]⁺=466.15, 468.15.

The intermediates in Table 21 below were prepared according Step 1 ofthe procedure to prepare Intermediate F.

TABLE 21 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)] ⁺ ¹H-NMRF-2-1

3-(4-[3-[(5- bromo- pentyl) oxy] propyl]- 3-methyl-2- oxo-1,3- benzo-diazol- 1-yl) piperidine- 2,6-dione 466.2 468.2 (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 6.97 (d, J = 4.6 Hz, 2H), 6.88 (q, J = 4.3 Hz, 1H), 5.37(dd, J = 12.6, 5.4 Hz, 1H), 3.55 (t, J = 6.8 Hz, 3H), 3.41 (dt, J =15.7, 6.2 Hz, 4H), 3.00-2.92 (m, 2H), 2.95-2.83 (m, 1H), 2.78- 2.61 (m,2H), 2.51 (p, J = 1.9 Hz, 2H), 2.05- 1.95 (m, 1H), 1.85-1.81 (m, 4H),1.55 (p, J = 6.4 Hz, 2H), 1.50-1.39 (m, 2H). F-2-2

3-(4-[3-[(2- bromo- ethoxy) propyl]-3- methyl-2- oxo-1,3- benzo- diazol-1-yl] piperidine- 2,6-dione 424.2 446.2 (400 MHz, DMSO-d₆) δ 11.10 (s,1H), 6.97 (d, J = 4.8 Hz, 2H), 6.97-6.86 (m, 1H), 5.37 (dd, J = 12.6,5.4 Hz, 1H), 3.74 (t, J = 5.6 Hz, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.52(t, J = 6.1 Hz, 2H), 3.33 (s, 1H), 3.03-2.95 (m, 2H), 2.90 (ddd, J =17.2, 12.9, 5.2 Hz, 1H), 2.72 (td, J = 12.8, 4.3 Hz, 1H), 2.63 (d, J =18.4 Hz, 1H), 2.05-1.96 (m, 1H), 1.85 (dq, J = 12.5, 6.3 Hz, 2H), 0.88(ddd, J = 24.3, 12.0, 6.7 Hz, 1H). F-2-3

3-[4-(4- bromo- butyl)- 3-methyl- 2-oxo- 1,3-benzo- diazol-yl]piperidine- 2,6-dione 394.2 396.2 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.02- 6.94 (m, 2H), 6.87 (dd, J = 5.8, 3.1 Hz, 1H), 5.37 (dd, J = 12.6,5.4 Hz, 1H), 3.60 (t, J = 6.7 Hz, 2H), 3.56 (s, 3H), 2.99-2.83 (m, 3H),2.77-2.58 (m, 2H), 2.06-1.97 (m, 1H), 1.92 (p, J = 6.8 Hz, 2H),1.78-1.66 (m, 2H). F-2-4

3-[4-(5- bromo- pentyl)- 3-methyl- 2-oxo-1,3- benzo- diazol- 1-yl]piperidine- 2,6-dione 408.1 410.1 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.01- 6.93 (m, 2H), 6.88 (dd, J = 5.4, 3.5 Hz, 1H), 5.37 (dd, J = 12.6,5.4 Hz, 1H), 3.58-3.54 (m, 4H), 2.89 (dt, J = 13.9, 6.7 Hz, 3H), 2.78-2.59 (m, 2H), 2.08 (s, 1H), 2.04-1.96 (m, 1H), 1.88 (p, J = 6.9 Hz, 2H),1.68-1.59 (m, 2H), 1.56-1.47 (m, 2H). F-2-5

tert-butyl N- [(3S,4R)-4- [(4-[3-[(5- bromo- pentyl) oxylpropyl] phenyl)methoxy]-1- carbamoyl pentan-3- yl] carbamate 565.5 567.5 (400 MHz,DMSO-d₆) δ 7.23 (d, J = 7.9 Hz, 3H), 7.15 (d, J = 7.8 Hz, 2H), 6.68 (s,1H), 6.61 (d, J = 9.1 Hz, 1H), 4.49-4.38 (m, 2H), 3.54 (t, J = 6.7 Hz,2H), 3.43-3.28 (m, 6H), 2.60 (t, J = 7.6 Hz, 2H), 2.04 (ddd, J = 15.2,9.5, 5.6 Hz, 1H), 1.88-1.72 (m, 6H), 1.58- 1.40 (m, 4H), 1.39 (s, 9H),1.36 (s, 1H), 1.06 (d, J = 6.0 Hz, 3H). F-2-6

tert-butyl N- [(3S,4R)-4- [[4-(4- bromo- butyl) phenyl] methoxy]- 1-carbamoyl pentan-3- yl] carbamate 471.2 473.2 (400 MHz, DMSO-d₆) δ7.31-7.02 (m, 5H), 6.67 (s, 1H), 6.60 (d, J = 9.1 Hz, 1H), 4.47 (s, 1H),4.44 (d, J = 4.3 Hz, 2H), 3.55 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.7 Hz,2H), 2.59 (q, J = 7.0, 6.4 Hz, 2H), 2.13-1.96 (m, 2H), 1.81 (t, J = 7.5Hz, 2H), 1.68 (p, J = 7.4 Hz, 2H), 1.48-1.45 (m, 1H), 1.39 (s, 9H), 1.06(d, J = 6.0 Hz, 3H). F-2-7

tert-butyl N- [(3S,4R)-4- [[4-(5- bromo- pentyl) phenyl] methoxy]- 1-carbamoyl pentan-3- yl] carbamate 485.3 487.3 (400 MHz, CDCl₃) δ 7.26(d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 6.47 (s, 1H), 5.36 (s,1H), 4.90 (d, J = 9.6 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.40 (d, J =11.5 Hz, 1H), 3.73- 3.59 (m, 2H), 3.43 (t, J = 6.8 Hz, 2H), 2.64 (t, J =7.7 Hz, 2H), 2.30 (ddd, J = 8.5, 6.2, 2.9 Hz, 2H), 2.01 (dd, J = 14.8,7.2 Hz, 1H), 1.96-1.88 (m, 2H), 1.72 (dd, J = 10.0, 4.9 Hz, 1H), 1.66(td, J = 9.0, 8.4, 5.1 Hz, 2H), 1.50 (t, J = 7.6 Hz, 2H), 1.46 (s, 9H),1.22 (d, J = 6.2 Hz, 3H). F-2-8

tert-butyl N- [(3S,4R)- 4-[[4-(3- [2-[2- (2-bromo- ethoxy) ethoxy]ethoxy] propyl) phenyl] methoxy]- 1- carbamoyl pentan- 3-yl] carbamate589.4 571.4 (400 MHz, CDCl₃) δ 7.25 (d, J = 7.8 Hz, 2H), 7.19 (d, J =8.0 Hz, 2H), 6.48 (s, 1H), 5.37 (s, 1H), 4.90 (d, J = 9.7 Hz, 1H), 4.59(d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 3.84 (t, J = 6.3 Hz,2H), 3.76-3.57 (m, 9H), 3.49 (td, J = 6.4, 2.1 Hz, 4H), 2.73-2.64 (m,2H), 2.36-2.20 (m, 2H), 2.15-1.61 (m, 5H), 1.46 (s, 9H), 1.22 (d, J =6.3 Hz, 3H). F-2-9

tert-butyl N- [(3S,4R)- 4-[[4-(1- bromo- 3,6,9,12- tetraoxa- penta-decan-15- yl)phenyl] methoxy]- 1- carbamoyl pentan-3- yl] carbamate633.4 635.4 (400 MHz, CDCl₃) δ 7.25 (d, J = 7.9 Hz, 2H), 7.19 (d, J =7.9 Hz, 2H), 6.72 (s, 1H), 5.60 (s, 1H), 4.92 (d, J = 9.5 Hz, 1H), 4.59(d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.83 (t, J = 6.3 Hz,2H), 3.73-3.65 (m, 11H), 3.58- 3.54 (m, 3H), 3.51-3.46 (m, 4H),2.74-2.66 (m, 2H), 2.30 (h, J = 8.0 Hz, 2H), 2.04-1.86 (m, 3H), 1.72 (s,1H), 1.46 (s, 9H), 1.22 (d, J = 6.2 Hz, 3H). F-2-10

tert-butyl N- [(3S,4R)- 4-[[4-(1- bromo- 3,6,9,12,15- penta- oxaocta-decan-18- yl)phenyl] methoxy]- 1- carbamoyl- pentan-3- yl] carbamate677.3 679.3 (400 MHz, CDCl₃) δ 7.25 (d, J = 7.7 Hz, 2H), 7.19 (d, J =7.8 Hz, 2H), 6.55 (s, 1H), 5.43 (s, 1H), 4.91 (d, J = 9.9 Hz, 1H), 4.59(d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.83 (t, J = 6.3 Hz,2H), 3.70-3.68 (m, 14H), 3.62- 3.60 (m, 3H), 3.51-3.49 (m, 4H), 2.70 (t,J = 7.7 Hz, 2H), 2.34-2.25 (m, 2H), 2.05-1.97 (m, 1H), 1.96-1.86 (m,3H), 1.76-1.67 (m, 1H), 1.46 (s, 9H), 1.22 (d, J = 6.3 Hz, 3H). F-2-11

tert-butyl N- [(3S,4R)-4- [[4-(3- bromo- propyl) phenyl] methoxy]-1-carbamoyl- pentan-3- yl] carbamate 457.1 459.1 (400 MHz, DMSO-d₆) δ7.30-7.13 (m, 5H), 6.73-6.55 (m, 2H), 4.43 (t, J = 8.2 Hz, 2H),3.50-3.35 (m, 4H), 2.70 (t, J = 7.5 Hz, 2H), 2.14-1.96 (m, 4H), 1.79(dtd, J = 13.2, 9.7, 8.6, 4.8 Hz, 1H), 1.49 (dd, J = 14.0, 8.8 Hz, 1H),1.39 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H). F-2-12

tert-butyl N- [(3S,4R)-4- ([4-[3-(2- bromo- ethoxy) propyl] phenyl]methoxy)-1- carbamoyl- pentan-3- yl] carbamate 501.2 503.2 (400 MHz,CDCl₃) δ 7.26 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.48 (s,1H), 5.34 (d, J = 11.4 Hz, 1H), 4.90 (d, J = 9.7 Hz, 1H), 4.59 (d, J =11.5 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 3.77 (t, J = 6.2 Hz, 2H), 3.73(s, 1H), 3.52-3.41 (m, 4H), 2.73 (t, J = 7.6 Hz, 2H), 2.32-2.26 (m, 2H),2.01 (dd, J = 14.0, 7.1 Hz, 1H), 1.96-1.89 (m, 2H), 1.70 (dd, J = 13.9,5.8 Hz, 1H), 1.46 (s, 9H), 1.22 (d, J = 6.3 Hz, 3H). F-2-13

tert-butyl N- [(3S,4R)- 4-[(4-[3- [2-(2- bromo- ethoxy) ethoxy] propyl]phenyl) methoxy]- 1- carbamoyl- pentan-3- yl] carbamate [(M + 23)]⁺ =567.3 569.3 (400 MHz, DMSO-d₆) δ 7.25-7.20 (m, 3H), 7.15 (d, J = 7.8 Hz,2H), 6.67 (s, 1H), 6.60 (d, J = 9.0 Hz, 1H), 4.49-4.39 (m, 2H), 3.75(td, J = 5.8, 1.9 Hz, 2H), 3.61-3.55 (m, 4H), 3.50 (dd, J = 6.0, 3.5 Hz,2H), 3.41-3.37 (m, 4H), 2.60 (t, J = 7.8 Hz, 2H), 2.04 (dt, J= 15.0, 9.3Hz, 2H), 1.81-1.76 (m, 3H), 1.47 (s, 1H), 1.38 (s, 9H), 1.06 (d, J = 6.0Hz, 3H) F-2-14

3-[5-(4- bromo- butyl)- 3-methyl- 2-oxo-1,3- benzo- diazol- 1-yl]piperidine- 2,6-dione 394.1, 396.1 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H),7.06- 6.99 (m, 2H), 6.88 (dd, J = 8.1, 1.6 Hz, 1H), 5.35 (dd, J = 12.7,5.3 Hz, 1H), 3.56 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 2.97-2.84 (m, 1H),2.78-2.57 (m, 4H), 2.01 (tq, J = 8.9, 3.5, 2.9 Hz, 1H), 1.88-1.77 (m,2H), 1.72 (p, J = 7.0, 6.4 Hz, 2H). F-2-15

3-[5-(6- bromo- hexyl)- 3-methyl-2- oxo-1,3- benzo- diazol- 1-yl]piperidine- 2,6-dione 422.2, 424.2 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.11- 6.96 (m, 2H), 6.87 (d, J = 7.7 Hz, 1H), 5.34 (dd, J = 12.7, 5.3Hz, 1H), 3.53 (t, J = 6.7 Hz, 2H), 3.33 (s, 3H), 2.98-2.84 (m, 1H), 2.72(td, J = 12.9, 4.3 Hz, 1H), 2.67-2.58 (m, 3H), 2.07-1.98 (m, 1H), 1.81(p, J = 6.9 Hz, 2H), 1.61 (p, J = 7.5 Hz, 2H), 1.43 (t, J = 7.8 Hz, 2H),1.34 (q, J = 7.1 Hz, 2H). F-2-16

tert-butyl 3- [(1r,4r)-4- (bromo- methyl) cyclo- hexyl] propanoate N/A(400 MHz, DMSO-d₆) δ 3.41 (d, J = 6.2 Hz, 2H), 3.25 (t, J = 6.5 Hz, 1H),2.19 (t, J = 7.7 Hz, 2H), 1.86-1.78 (m, 2H), 1.77-1.68 (m, 2H),1.59-1.47 (m, 1H), 1.47-1.41 (m, 1H), 1.39 (s, 9H), 1.20-1.13 (m, 1H),1.04-0.84 (m, 4H) F-2-17

methyl 2-[3- (bromo- methyl) cyclobutyl] acetate N/A (400 MHz, CD₃OD) δ3.68-3.64 (m, 3H), 3.55-3.42 (m, 2H), 2.77-2.39 (m, 4H), 2.32- 2.28 (m,1H), 2.08-1.85 (m, 2H), 1.49-1.45 (m, 1H) F-2-18

Methyl 2-(3- bromo- cyclobutyl) acetate N/A (400 MHz, CD₃OD) δ 4.40-3.87(m, 1H), 3.52 (d, J = 1.8 Hz, 3H), 2.66-2.41 (m, 1H), 2.42, (dd, J =7.2, 2.2 Hz, 2H), 2.07-2.01 (m, 2H), 1.65-1.48 (m, 2H) F-2-19

3-[5-(7- bromo- heptyl)- 3-methyl- 2-oxo-1,3- benzo- diazol- 1-yl]piperidine- 2,6-dione 436.1, 438.1 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.10- 6.94 (m, 2H), 6.87 (dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J = 12.7,5.4 Hz, 1H), 3.53 (t, J = 6.7 Hz, 2H), 3.33 (s, 3H), 3.00-2.90 (m, 1H),2.72 (td, J = 12.9, 4.3 Hz, 1H), 2.66-2.56 (m, 3H), 2.01 (ddd, J = 10.9,5.8, 3.6 Hz, 1H), 1.79 (p, J = 6.8 Hz, 2H), 1.60 (p, J = 7.0 Hz, 2H),1.41-1.27 (m, 6H) F-2-20

tert-butyl 5-(3- bromo- cyclobutyl) pentanoate N/A (400 MHz,Chloroform-d) δ 4.60-4.51 (m, 1H), 2.64-2.50 (m, 3H), 2.40-2.29 (m, 2H),2.22 (t, J = 7.4 Hz, 2H), 1.62-1.54 (m, 3H), 1.50-1.48 (m, 1H), 1.46 (s,9H), 1.31-1.19 (m, 2H) F-2-21

(4-bromo- 3-methyl- phenyl) methanol 201.0, 203.0 (400 MHz, DMSO-d₆) δ7.51 (d, J = 8.2 Hz, 1H), 7.29 (dd, J = 2.1, 1.0 Hz, 1H), 7.08 (dd, J =8.2, 2.1 Hz, 1H), 5.24 (s, 1H), 4.44 (s,2H), 2.34 (s, 3H) F-2-22

tert-butyl 4- (3-bromo- cyclobutyl) butanoate N/A (400 MHz, DMSO-d₆) δ4.72-4.68 (m, 0.7H), 4.51-4.47 (m, 0.3H), 2.87-2.65 (m, 0.3H), 2.49-2.43(m, 0.7H), 2.40-2.27 (m, 1H), 2.25-2.12 (m, 2H), 2.10-1.97 (m, 1H),1.66- 1.51 (m, 1H), 1.46-1.26 (m, 13H), 1.33-1.20 (m, 1H). F-2-23

benzyl 4-(4- bromo- cyclohexyl) butanoate N/A (300 MHz, CD₃OD) δ7.37-7.31 (m, 5H), 4.85-4.84 (m, 2H) 4.63 (d, J = 5.2 Hz, 1H), 2.39-2.28(m, 2H), 2.05-1.99 (m, 2H), 1.88- 1.83 (m, 2H), 1.69-1.48 (m, 6H),1.30-1.25 (m, 3H) F-2-24

tert-butyl 3-(4- bromo- cyclohexyl) propanoate N/A (400 MHz, CDCl₃) δ4.73-4.60 (m, 2H), 2.53-2.41 (m, 1H), 2.33-2.23 (m, 2H), 2.26- 2.05, (m,2H), 2.03-1.92 (m 3H) 1.90-1.86 (m, 1H), 1.65-1.50 (m, 3H), 1.47 (s,9H).

Step 2. Tert-butylN-[(3S,4R)-1-carbamoyl-4-[[4-(5-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]pentyl)phenyl]methoxy]pentan-3-yl]carbamate(Intermediate F′). To a mixture of3-(5-[3-[(5-bromopentyl)oxy]propyl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione(420 mg, 0.90 mmol), tert-butylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(449 mg, 1.08 mmol), tris(trimethylsilyl)silane (224 mg, 0.90 mmol),Na₂CO₃ (286 mg, 2.70 mmol) and IR[DF(CF₃)PPY]₂ (DTBPY)PF₆ (10 mg, 0.01mmol) in DME (6.00 mL) was added dtbbpy (2.40 mg, 0.01 mmol) and1,2-dimethoxyethane dihydrochloride nickel (2.00 mg, 0.01 mmol) in DME(6.00 mL) at room temperature under nitrogen atmosphere. The mixture wasstirred for 4 hours under 34 W blue LED at room temperature. Theresulting mixture was filtered. The filter cake was washed with DCM(3×15.0 mL). The filtrate was concentrated under reduced pressure. Theresidue was purified by reversed phase Flash chromatography with thefollowing conditions: Column: WelFlash™ C18-I, 20-40 um, 330 g; EluentA: water (plus 10 mmol/L HOAc); Eluent B: ACN; Gradient: 50%-75% B in 25min; Flow rate: 80 mL/min; Detector: UV 220/254 nm; desired fractionswere collected at 70% B and concentrated under reduced pressure toafford the title compound as a yellow solid (290 mg, 45%): ¹H NMR (400MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.24-7.21 (m, 3H), 7.14 (d, J=7.9 Hz,2H), 7.06-7.00 (m, 2H), 6.86 (dd, J=8.1, 1.6 Hz, 1H), 6.68 (s, 1H), 6.60(d, J=9.1 Hz, 1H), 5.34 (dd, J=12.7, 5.4 Hz, 1H), 4.47-4.37 (m, 2H),3.49-3.32 (m, 9H), 2.90 (ddd, J=16.9, 12.8, 5.1 Hz, 1H), 2.77-2.53 (m,7H), 2.04-1.94 (m, 2H), 1.82-1.77 (m, 3H), 1.60-1.50 (m, 5H), 1.38 (s,11H), 1.05 (d, J=6.0 Hz, 3H); MS (ESI, m/z): [(M+1)]⁺=722.40.

The following intermediates in Table 22 were prepared according to Step2 of the procedure to prepare Intermediate F.

TABLE 22 Characterization data for intermediates prepared according toabove. Inter- MS: me- Chemical [(M + diate Structure Name 1)]⁺ ¹H-NMR F1

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4- (5-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl- 2-oxo-1,3- benzodiazol-4- yl]propoxylpentyl)phenyl] methoxy] pentan-3-yl] carbamate 722.6 ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 7.24-7.20 (m, 3H), 7.14 (d, J = 7.8 Hz, 2H),6.99-6.92 (m, 2H), 6.86 (dd, J = 5.6, 3.4 Hz, 1H), 6.68 (s, 1H), 6.60(d, J = 9.1 Hz, 1H), 5.37 (dd, J = 12.7, 5.5 Hz, 1H), 4.47-4.36 (m, 2H),3.45- 3.30 (m, 7H), 2.98-2.83 (m, 3H), 2.72 (td, J = 12.9, 4.4 Hz, 1H),2.67-2.52 (m, 3H), 2.10-2.00 (m, 1H), 2.01 (s, 3H), 1.86-1.76 (m, 3H),1.64-1.54 (m, 2H), 1.56-1.45 (m, 2H), 1.38 (s, 13H), 1.05 (dd, J = 6.1,2.0 Hz, 3H). F2

tert-butyl N- [(3S,4R)-1- carbamoyl-4- [[4-(2-[3- [1-(2,6-dioxopiperidin- 3-yl)-3- methyl-2- oxo-1,3- benzodiazol-4- yl]propoxy]ethyl)phenyl] methoxy] pentan- 3-yl]carbamate 680.4 ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 7.26-7.22 (m, 5H), 6.98-6.90 (m, 2H), 6.81(dd, J = 6.4, 2.5 Hz, 1H), 6.70- 6.65 (m, 1H), 6.60 (d, J = 9.1 Hz, 1H),5.36 (dd, J = 12.6, 5.3 Hz, 1H), 4.49-4.38 (m, 2H), 3.59 (t, J = 6.8 Hz,2H), 3.45- 3.36 (m, 4H), 3.32 (s, 1H), 2.96-2.88 (m, 4H), 2.83 (dt, J =13.6, 6.1 Hz, 2H), 2.78- 2.62 (m, 2H), 2.08 (s, 2H), 1.87-1.77 (m, 1H),1.81 (s, 3H), 1.38 (s, 10H), 1.05 (d, J = 6.0 Hz, 3H). F3

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4-[4- [1-(2,6- dioxo-piperidin- 3-yl)-3- methyl- 2-oxo-1,3- benzodiazol- 4-yl]butyl] phenyl)methoxy] pentan-3- yl] carbamate 650.5 ¹H NMR (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 7.28-7.09 (m, 5H), 6.99-6.91 (m, 2H), 6.85 (dd, J = 6.4, 2.5Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 9.2 Hz, 1H), 5.36 (dd, J = 12.6, 5.4Hz, 1H), 4.48-4.39 (m, 2H), 3.48-3.36 (m, 2H), 2.99-2.82 (m, 3H), 2.72(td, J = 12.9, 4.4 Hz, 1H), 2.67- 2.57 (m, 3H), 2.07-1.96 (m, 2H), 1.79(tdt, J = 9.4, 5.6, 2.7 Hz, 1H), 1.74-1.57 (m, 4H), 1.54-1.44 (m, 2H),1.38 (s, 11H), 1.06 (d, J = 5.9 Hz, 3H). F4

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4-[5- [1-(2,6- dioxo-piperidin- 3-yl)-3- methyl-2- oxo-1,3- benzodiazol- 4-yl]pentyl] phenyl)methoxy] pentan-3- yl] carbamate 664.5 ¹HNMR (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 7.23 (d, J = 7.8 Hz, 3H), 7.14 (d, J = 7.8 Hz, 2H), 7.00-6.91(m, 2H), 6.85 (dd, J = 5.9, 3.0 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J = 9.1Hz, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 4.49-4.38 (m, 2H), 3.54 (s,3H), 3.49-3.35 (m, 2H), 2.92- 2.88 (m, 3H), 2.77-2.55 (m, 4H), 2.14-1.96 (m, 3H), 1.85-1.75 (m, 1H), 1.67- 1.59 (m, 4H), 1.39 (s, 12H), 1.06(d, J = 6.1 Hz, 3H). F5

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-([4-[3-([5- [1-(2,6- dioxo-piperidin- 3-yl)-3- methyl- 2-oxo-1,3- benzodiazol- 5-yl] pentyl]oxy)propyl] phenyl] methoxy) pentan-3- yl] carbamate 722.6 ¹H NMR (400 MHz,DMSO-d₆) δ 11.07 (s, 1H), 7.24-7.22 (m, 3H), 7.13 (d, J = 7.8 Hz, 2H),7.05-6.97 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 6.60 (d, J =9.2 Hz, 1H), 5.33 (dd, J = 12.8, 5.4 Hz, 1H), 4.47-4.38 (m, 2H), 3.37(dd, J = 26.7, 6.4 Hz, 9H), 2.88 (d, J = 16.7 Hz, 1H), 2.76-2.55 (m,6H), 2.10-1.96 (m, 3H), 1.78-1.73 (m, 3H), 1.64-1.60 (m, 2H), 1.55-1.52(m, 2H), 1.38 (s, 12H), 1.06 (d, J = 6.0 Hz, 3H). F6

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-([4-[3-([5- [1-(2,6- dioxo-piperidin- 3-yl)-3- methyl- 2-oxo-1,3- benzodiazol- 4-yl] pentyl] oxy)propyl] phenyl] methoxy) pentan- 3-yl] carbamate 722.5 ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 7.25-7.22 (m, 3H), 7.14 (d, J = 7.8 Hz, 2H),6.99-6.92 (m, 2H), 6.88 (q, J = 4.8 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J =9.0 Hz, 1H), 5.36 (dd, J = 12.4, 5.3 Hz, 1H), 4.48-4.39 (m, 2H), 3.56(s, 3H), 3.48-3.32 (m, 6H), 2.96-2.82 (m, 3H), 2.76-2.56 (m, 4H),2.09-1.95 (m, 3H), 1.80-1.76 (m, 3H), 1.61-1.57 (m, 4H), 1.46-1.44 (m,3H), 1.39 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H). F15

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4- [4-[1-(2,6- dioxo-piperidin-3- yl)-3- methyl- 2-oxo-1,3- benzodiazol- 5-yl] butyl] phenyl)methoxy] pentan- 3-yl] carbamate 650.2 Used in the next step withoutfurther purification F16

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4-[6- [1-(2,6- dioxo-piperidin- 3-yl)-3- methyl- 2-oxo-1,3- benzodiazol- 5-yl] hexyl] phenyl)methoxy] pentan- 3-yl] carbamate 678.5 ¹H NMR (400 MHz, DMSO-d₆) δ 11.07(s, 1H), 7.21 (m, 3H), 7.12 (d, J = 7.9 Hz, 2H), 7.03-6.96 (m, 2H), 6.85(dd, J = 8.1, 1.6 Hz, 1H), 6.67 (s, 1H), 6.60 (d, J = 9.1 Hz, 1H), 5.33(dd, J = 12.7, 5.4 Hz, 1H), 4.47-4.37 (m, 2H), 3.41 (dq, J = 15.9, 6.2Hz, 1H), 3.31 (s, 3H), 2.98-2.84 (m, 1H), 2.77-2.50 (m, 7H), 2.12-1.94(m, 2H), 1.78 (dddd, J = 13.1, 9.4, 5.9, 2.9 Hz, 1H), 1.63-1.51 (m, 4H),1.50-1.40 (m, 1H), 1.38 (s, 9H), 1.34-1.27 (m, 5H), 1.05 (d, J = 6.0 Hz,3H). F17

methyl 4-[6- ([[(2R,3S)- 3-[tert- butoxy- carbonyl) amino]-5- carbamoyl-pentan- 2-yl]oxy] methyl) naphthalen- 2-yl] butanoate 487.20 (400 MHz,CD₃OD) δ 7.83-7.75 (m, 3H), 7.64 (d, J = 1.5 Hz, 1H), 7.49 (dd, J = 8.4,1.7 Hz, 1H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 4.75 (d, J = 11.8 Hz, 1H),4.66 (d, J = 11.8 Hz, 1H), 3.66 (s, 3H), 3.69- 3.52 (m, 2H), 2.82 (t, J= 7.6 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 2.35-2.18 (m, 2H), 2.09-1.95(m, 3H), 1.65 (dtd, J = 15.1, 9.9, 5.9 Hz, 1H), 1.41 (s, 9H), 1.22 (d, J= 6.0 Hz, 3H) F18

methyl 4-[6- ([[(2R,3S)- 3-(tert-butoxy- carbonyl) amino]-5- carbamoyl-pentan-2-yl] oxy]methyl) naphthalen- 1-yl] butanoate 487.2 (400 MHz,DMSO-d₆) δ 8.07 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.77-7.65 (m, 1H), 7.52 (dd, J = 8.7, 1.8 Hz, 1H), 7.42 (dd,J = 8.2, 7.0 Hz,1H), 7.32 (dd, J = 7.0, 1.3 Hz, 1H), 7.24 (s, 1H), 6.72-6.63 (m, 2H),4.72-4.60 (m, 2H), 4.23 (t, J = 6.5 Hz, 2H), 3.60 (s, 3H), 3.54-3.46 (m,2H), 3.09-3.03 (m, 2H), 2.09-2.05 (m, 2H), 1.66-1.64 (m, 2H), 1.37 (s,9H), 1.25-1.23 (m, 1H), 1.18- 1.15 (m, 1H), 1.11 (d, J = 5.8 Hz, 3H).F19

methyl 4-(4- [[(tert- butoxy- carbonyl) amino] methyl] phenyl) butanoate[(M + NH₄)]⁺ = 325.20 (400 MHz, DMSO-d₆) δ 7.33 (t, J = 6.5 Hz, 1H),7.17-7.09 (m, 4H), 4.08 (d, J = 6.1 Hz, 2H), 3.57 (s, 3H), 2.58-2.51 (m,2H), 2.29 (t, J = 7.4 Hz, 2H), 1.88-1.75 (m, 2H), 1.39 (s, 9H) F20

tert-butyl 3- [(1r,4r)- 4-[[1-(2,6- dioxo- piperidin- 3-yl)-3- methyl-2-oxo-1,3- benzodiazol- 5-yl]methyl] cyclohexyl] propanoate [(M − H)]⁻ =485.05 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 6.99 (d, J = 8.0 Hz, 2H),6.82 (dd, J = 8.0, 1.6 Hz, 1H), 5.36-5.32 (m, 1H), 3.31 (s, 3H),2.97-2.85 (m, 1H), 2.78-2.59 (m, 2H), 2.48 (s, 1H), 2.17 (t, J = 7.6 Hz,2H), 2.06-1.94 (m, 1H), 1.70-1.64 (m, 4H), 1.47-1.41 (m, 1H), 1.39 (s,9H), 1.36 (d, J = 7.6 Hz, 2H), 1.24 (d, J = 6.7 Hz, 1H), 1.20-1.13 (m,1H), 1.00-0.75 (m, 4H) F21

methyl 2- (3-[[4- ([[(2R,3S)- 3-[(tert- butoxy- carbonyl) amino]-5-carbamoyl- pentan-2- yl]xy] methyl) phenyl] methyl] cyclobutyl) acetate477.30 (400 MHz, CD₃OD) δ 7.27 (dd, J = 8.1, 2.1 Hz, 2H), 7.13 (t, J =8.7 Hz, 2H), 4.62-4.44 (m, 2H), 3.64 s, 3H), 3.63-3.56 (m, 1H),3.52-3.49 (m, 1H), 2.81-2.62 (m, 2H), 2.62-2.54 (m, 1H), 2.53-2.35 (m,3H), 2.35-2.15 (m, 4H), 2.06-1.89 (m, 2H), 1.87-1.76 (m, 1H), 1.69-1.57(m, 1H), 1.46 (s, 9H), 1.17 (s, 3H) F22

Methyl 2- [3-[4- ([[(2R,3S)- 3-[(tert- butoxy- carbonyl) amino]-5-carbamoyl- pentan- 2-yl]oxy] methyl) phenyl] cyclobutyl] acetate 463.45(400 MHz, CD₃OD) δ 7.35-7.28 (m, 2H), 7.26-7.12 (m, 2H), 4.68-4.38 (m,2H), 3.67 s, 3H), 3.67-3.56 (m, 1H), 3.57-3.46 (m, 1H), 3.46-3.34 (m,1H), 2.75-2.42 (m, 4H), 2.36-2.32 (m, 1H), 2.25-2.13 (m, 1H), 2.05 (s,2H), 2.04-1.93 (m, 1H), 1.88-1.76 (m, 1H), 1.69-1.59 (m, 1H), 1.45 (s,9H), 1.20 (s, 3H) F23

tert-butyl 4- [[1-(2,6- dioxo- piperidin- 3-yl)-3- methyl- 2-oxo-1,3-benzodiazol- 5-yl]methyl] piperidine-1- carboxylate 456.95 (400 MHz,DMSO-d6) δ 11.08 (s, 1H), 7.03-6.94 (m, 2H), 6.84 (dd, J = 8.0, 1.5 Hz,1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 3.92 (d, J = 13.0 Hz, 2H), 2.90(m, 1H), 2.77-2.57 (m, 4H), 2.54 (m, 4H), 2.05- 1.95 (m, 2H), 1.77-1.60(m, 1H), 1.61- 1.52 (m, 2H), 1.39 (s, 9H), 1.10-0.96 (m, 2H) F24

tert-butyl 4- [1-(2,6- dioxo- piperidin- 3-yl)-3- methyl- 2-oxo-1,3-benzodiazol- 5-yl] piperidine-1- carboxylate 443.20 (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 7.12 (d, J = 1.7 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92(dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.10 (d, J =12.9 Hz, 2H), 3.34 (s, 3H), 2.99-2.57 (m, 6H), 2.05-1.98 (m, 1H),1.80-1.71 (m, 2H), 1.56 (tt, J = 12.7, 6.4 Hz, 2H), 1.43 (s, 9H) F25

benzyl 4-[[4- ([[2R,3S)- 3-(tert- butoxy- carbonyl) amino]-5- carbamoyl-pentan- 2-yl]oxy] methyl) phenyl] methyl] piperidine-1- carboxylate568.30 (400 MHz, DMSO-d₆) δ 7.43-7.28 (m, 6H), 7.24 (d, J = 8.0 Hz, 2H),7.12 (d, J = 8.0 Hz, 2H), 6.68 (s, 1H), 6.61 (d, J = 9.1 Hz, 1H), 5.06(d, J = 2.5 Hz, 2H), 4.49-4.34 (m, 1H), 4.02-3.96 (m, 4H), 3.55-3.37 (m,1H), 2.72 (d, J = 31.2 Hz, 4H), 2.06-2.02 (m, 1H), 1.83-1.68 (m, 1H),1.65-1.42 (m, 4H), 1.39 (s, 9H), 1.11-0.93 (m, 6H) F26

tert-butyl N- [(2S,11S)-2- [[(1S)-3- carbamoyl-1- (diphenyl- methyl-carbamoyl) propyl] carbamoyl]- 6-[7-[1-(2,6- dioxo- piperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol- 5-yl]heptyl]- 12-oxo-1- azatricyclo-[6.4.1.0^(∧) [4,13]] trideca- 4(13),5,7- trien-11- yl]carbamate 995.40(400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.20-8.14(m, 3H), 7.36-7.19 (m, 9H), 7.04-6.97 (m, 2H), 6.91-6.81 (m, 3H),6.75-6.73 (m, 1H), 6.66 (s, 1H), 6.03-5.98 (m, 1H), 5.36-5.32 (m, 3H),5.12 (m, 1H), 4.33- 4.31 (m, 1H), 4.05-3.98 (m, 1H), 3.32 (s, 3H),3.04-3.01 (m, 2H), 2.87 (d, J = 18.0 Hz, 2H), 2.72-2.65 (m, 4H),2.22-1.89 (m, 7H), 1.58-1.45 (m, 4H), 1.39 (s, 9H), 1.33-1.25 (m, 7H)F27

methyl 4-[3- [(2S)-2-(tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy] phenyl] butanoate 409.30 (400 MHz, DMSO-d₆) δ 7.26 (s, 1H),7.23-7.14 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.75 (dt, J = 5.3, 2.7 Hz,3H), 6.72 (s, 1H), 3.87-3.83 (m, 2H), 3.71 (dd, J = 12.0, 5.1 Hz, 1H),3.59 (s, 3H), 2.56 (t, J = 7.6 Hz, 2H), 2.30 (t, J = 7.4 Hz, 2H),2.21-2.04 (m, 2H), 1.88-1.75 (m, 3H), 1.62-1.58 (m, 1H), 1.40 (s, 9H)F28

tert-butyl N- (2S,11S)-2- [[(1S)-3- carbamoyl-1- (diphenyl- methyl-carbamoyl) propyl] carbamoyl]- 6-[5-[1-(2,6- dioxo- piperidin-3-yl)-3-methyl- 2-oxo-1,3- benzodiazol- 5-yl]pentyl]- 12-oxo-1-azatricyclo [6.4.1.0^(∧) [4, 13]] trideca- 4(13),5,7- trien-11- yl]carbamate 967.60 (300 MHz, Chloroform-d) δ 9.07-8.70 (m, 1H), 7.92-7.78(m, 2H), 7.35-7.30 (m, 2H), 7.26-7.11 (m, 4H), 6.91-6.69 (m, 4H), 6.26(d, J = 8.3 Hz, 1H), 5.92- 5.84 (m, 2H), 5.28-5.17 (m, 1H), 5.12 (dd, J= 11.0, 3.4 Hz, 1H), 4.58-4.51 (m, 2H), 4.27 (s, 1H), 3.41 (s, 3H),3.37-3.25 (m, 1H), 3.20-3.05 (m, 2H), 2.95-2.59 (m, 4H), 2.53 (t, J =7.4 Hz, 1H), 2.29- 2.18 (m, 6H), 2.10-2.00 (m, 2H), 1.71- 1.57 (m, 4H),1.49-1.47 (m, 13H), 1.38- 1.29 (m, 5H) F29

tert-butyl 5- [3-[1-(2,6- dioxo- piperidin- 3-yl)-3- methyl-2- oxo-1,3-benzodiazol- 5-yl] cyclobutyl] pentanoate 470.20 (400 MHz, Chloroform-d)δ 8.37 (s, 1H), 6.99-6.83 (m, 2H), 6.74 (dd, J = 8.1, 6.3 Hz, 1H),5.27-5.22 (m, 1H), 3.67-3.59 (m, 1H), 3.46 (d, J = 1.4 Hz, 3H), 3.42-3.33 (m, 1H), 3.00-2.65 (m, 3H), 2.56- 2.48 (m, 1H), 2.32-2.18 (m, 3H),2.16- 2.07 (m, 1H), 1.74-1.54 (m, 4H), 1.47 (d, J = 2.3 Hz, 9H),1.45-1.39 (m, 2H), 1.39- 1.23 (m, 2H) F30

tert-butyl 4- [3-[1-(2,6- dioxo- piperidin- 3-yl)-3- methyl-2- oxo-1,3-benzodiazol- 5-yl] cyclobutyl] butanoate 456.20 (400 MHz, Methanol-d₄) δ7.13-6.93 (m, 3H), 5.37-5.27 (m, 1H), 4.59 (s, 2H), 3.73-3.55 (m, 1H),3.46-3.44 (m, 3H), 3.01-2.87 (m, 1H), 2.87-2.74 (m, 2H), 2.55 (dt, J =10.4, 7.8 Hz, 1H), 2.36-2.04 (m, 5H), 1.75-1.73 (m, 1H), 1.68-1.52 (m,2H), 1.49-1.46 (m, 12H). F31

tert-butyl N- [(2S,11S)-2- [[(1S)-3- carbamoyl-1- (diphenyl- methyl-carbamoyl) propyl] carbamoyl]- 6-[6-[1-(2,6- dioxo- piperidin-3-yl)-3-methyl- 2-oxo-1,3- benzodiazol- 5-yl]hexyl]- 12-oxo-l- azatricyclo[6.4.1.0^(∧) [4,13]] trideca- 4(13),5,7- trien-11-yl] carbamate 981.65(400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.79 (d, J = 8.5 Hz, 1H), 8.19 (d, J= 8.0 Hz, 1H), 7.38-7.16 (m, 13H), 7.05-6.96 m, 3H), 6.91-6.83 (m, 3H),6.75 (s, 1H), 6.08 (d, J = 8.3 Hz, 1H), 5.34 (dd, J = 12.8, 5.3 Hz, 1H),5.08 (dd, J = 11.0, 2.9 Hz, 1H), 4.36-4.30 (m, 1H), 4.04-4.00 (m, 1H),3.32 (s, 3H), 3.04-2.86 (m, 2H), 2.76-2.58 (m, 3H), 2.17-1.95 (m, 6H),1.91-1.76 (m, 1H), 1.63-1.52 (m, 3H), 1.39 (s, 9H), 1.35-1.24 (m, 9H)F32

methyl 4- [3-[(2S)-2- (tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy]-2- fluoro- phenyl] butanoate 427.20 (300 MHz, DMSO-d₆) δ7.29-7.27 (m, 1H), 7.03 (d, J = 5.8 Hz, 2H), 6.83 (d, J = 9.6 Hz, 2H),6.77-6.74 (m, 1H), 3.93 (d, J = 6.0 Hz, 2H), 3.75-3.73 (m, 1H), 3.34 (d,J = 1.2 Hz, 1H), 2.64-2.59 (m, 2H), 2.33-2.31 (m, 3H), 2.15-2.12 (m,2H), 1.84-1.81 (m, 3H), 1.62 (d, J = 10.3 Hz, 1H), 1.54-1.51 (m, 1H),1.40 (s, 9H) F33

tert-butyl N- [(2S,11S)-2- [[(1S)-3- carbamoyl- 1-[[(4- isopropyl-phenyl) methyl] carbamoyl] propyl] carbamoyl]- 6-[6-[1-(2,6- dioxo-piperidin-3- yl)-3-methyl- 2-oxo-1,3- benzodiazol- 5-yl]hexyl]-12-oxo-1- azatricyclo [6.4.1.0^(∧) [4,13] trideca- 4(13),5,7- trien-11-yl] carbamate 947.25 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.34 (t, J =5.9 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.29-7.23 (m, 1H), 7.18-7.10 (m,4H), 7.06 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.99 (d, J =8.0 Hz, 1H), 6.90 (s, 1H), 6.88- 6.83 (m, 2H), 6.79-6.74 (m, 1H),5.35-5.32 (m, 1H), 5.10-5.07 (m, 1H), 4.22-4.18 (m, 3H), 4.05-3.99 (m,1H), 3.32 (s, 3H), 3.12- 2.97 (m, 2H), 2.96-2.88 (m, 2H), 2.87- 2.81 (m,1H), 2.77-2.56 (m, 5H), 2.49- 2.46 (m, 1H), 2.12-1.95 (m, 5H), 1.94-1.71 (m, 3H), 1.64-1.48 (m, 4H), 1.39 (s, 9H), 1.35-1.32 (m, 4H), 1.17(d, J = 6.9 Hz, 6H) F34

methyl 4-[3- [(2S)-2- [(tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy]- 2-fluoro-5- methyl- phenyl] butanoate 441.25 (300 MHz, DMSO-d₆)δ 7.25 (s, 1H), 6.80 (d, J = 8.1 Hz, 2H), 6.71 (s, 1H), 6.64-6.56 (m,1H), 3.88 (d, J = 6.0 Hz, 2H), 3.77-3.65 (m, 1H), 3.57 (s, 3H),2.59-2.52 (m, 2H), 2.22 (s, 3H), 2.17- 2.08 (m, 2H), 1.81-1.74 (m, 2H),1.49 (q, J = 7.0 Hz, 4H), 1.37 (s, 9H) F35

methyl 4-[3- [(2S)-2- [(tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy]-2- chloro- phenyl] butanoate 443.15 (400 MHz, DMSO-d₆) δ 7.27(s, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.00 (dd, J = 8.3, 1.4 Hz, 1H), 6.90(dd, J = 7.7, 1.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 3.93(d, J = 6.3 Hz, 2H), 3.77 (q, J = 7.2, 4.4 Hz, 1H), 3.59 (s, 3H), 2.71(dd, J = 8.7, 6.6 Hz, 2H), 2.34 (t, J = 7.4 Hz, 2H), 2.13 (tt, J = 14.7,7.3 Hz, 2H), 1.91- 1.76 (m, 3H), 1.39 (s, 9H), F36

methyl 4-[3- [(2S)-2- [(tert- butoxy- carbonyl) amino]-4- carbamoyl-butanamido]- 2-chloro- phenyl] butanoate 456.20 (400 MHz, DMSO-d₆) δ9.33 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.28 (td, J = 8.6, 7.8, 5.8 Hz,3H), 7.13 (dd, J = 7.6, 1.6 Hz, 1H), 6.84-6.79 (m, 1H), 4.15-4.09 (m,1H), 3.59 (s, 3H), 2.76-2.72 (m, 2H), 2.36 (t, J = 7.3 Hz, 2H), 2.20 (s,3H), 2.02-1.97 (m, 1H), 1.89-1.73 (m, 2H), 1.41 (s, 9H) F37

methyl 4-[3- [(2S)-2-[(tert- butoxy- carbonyl) amino]-4- carbamoyl-butanamido]- phenyl] butanoate 422.25 (400 MHz, DMSO-d₆) δ 9.89 (s, 1H),7.47-7.41 (m, 2H), 7.29 (s, 1H), 7.22 (dd, J = 8.6, 7.6 Hz, 1H), 7.03(d, J = 7.7 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.78 (s, 1H), 5.76 (s,1H), 4.08-3.98 (m, 1H), 3.59 (s, 3H), 2.56 (dd, J = 8.6, 6.7 Hz, 2H),2.33 (t, J = 7.4 Hz, 2H), 2.15-2.09 (m, 2H), 1.96-1.71 (m, 3H), 1.39 (s,9H) F38

methyl 4-[3- [(2S)-2- [(tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy]-2- fluoro- phenyl] butanoate 427.20 (400 MHz, DMSO-d₆) δ 7.27(s, 1H), 7.07-6.97 (m, 2H), 6.84-6.79 (m, 2H), 6.74 (s, 1H), 3.92 (d, J= 6.0 Hz, 2H), 3.76-3.72 (m, 1H), 3.58 (s, 3H), 2.61 (t, J = 7.6 Hz,2H), 2.32 (t, J = 7.4 Hz, 2H), 2.18-2.05 (m, 2H), 1.82-1.78 (m, 3H),1.64-1.52 (m, 1H), 1.39 (s, 9H) F39

benzyl 4- [(1r,4s)- 4-[1-(2,6- dioxo- piperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol- 5-yl] cyclohexyl] butanoate 518.30 (300 MHz,CDCl3) δ 8.03 (s, 1H), 7.36 (d, J = 10.7 Hz, 4H), 6.94 (d, J = 8.2 Hz,1H), 6.89-6.86 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.22-5.19 (m, 1H),5.16-5.14 (m, 2H), 3.44 (s, 3H), 3.00-2.68 (m, 3H), 2.62-2.60 (m, 1H),2.43-2.39 (m, 2H), 2.26-2.24 (m, 1H), 1.95-1.89 (m, 5H), 1.32-1.26 (m,5H), 0.93-0.84 (m, 4H) F40

tert-butyl 3- ((1s,4s)- 4-(1-(2,6- dioxo- piperidin-3- yl)-3-methyl-2-oxo- 2,3-dihydro- 1H-benzo[d] imidazol- 5-yl) cyclohexyl) propanoate470.30 (300 MHz, CDCl3) δ 8.39 (s, 1H), 6.98- 6.86 (m, 2H), 6.74 (d, J =8.0 Hz, 1H), 5.35-5.18 (m, 1H), 3.45 (s, 3H), 3.00- 2.88 (m, 1H),2.92-2.62 (m, 2H), 2.56- 2.52 (m, 1H), 2.35-2.18 (m, 3H), 1.95- 1.89 (m,4H), 1.73-1.70 (m, 1H), 1.60- 1.56 (m, 2H), 1.48 (s, 9H), 1.45-1.33 (m,4H), 1.25-1.02 (m, 2H). F41

benzyl 4- [(1s,4r)-4- [1-(2,6- dioxo- piperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol- 5-yl] cyclohexyl] butanoate 518.30 (300 MHz,CDCl3) δ 8.10 (s, 1H), 7.41- 7.36 (m, 4H), 7.34 (s, 1H), 6.97-6.85 (m,2H), 6.73 (d, J = 8.0 Hz, 1H), 5.21 (dd, J = 12.4, 5.2 Hz, 1H), 5.14 (s,2H), 3.44 (s, 3H), 3.00-2.64 (m, 3H), 2.51 (t, J = 12.4 Hz, 1H), 2.38(t, J = 7.5 Hz, 2H), 2.29- 2.17 (m, 1H), 1.93-1.85 (m, 4H), 1.75- 1.71(m, 3H), 1.51-1.45 (m, 1H), 1.32- 1.26 (m, 3H), 1.18-1.06 (m, 2H). F42

tert-butyl N- [(2S,11S)-2- [[(1S)-3- carbamoyl-1- (pyridin- 2-yl)propyl] carbamoyl]- 6-[6-[1- (2,6-dioxo- piperidin-3- yl)-3- methyl-2-oxo-1,3- benzodiazol- 5-yl]hexyl]- 12-oxo-1- azatricyclo [6.4.1.0^(∧)[4,13]] trideca- 4(13),5,7- trien-11- yl] carbamate 849.35 (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.47 (d, J = 8.0 Hz,1H), 7.78-7.72 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.26 (dd, J = 7.6, 4.8Hz, 1H), 7.19 (s, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.05-6.96 (m, 2H),6.91-6.81 (m, 3H), 6.70 (s, 1H), 5.34 (dd, J = 12.6, 5.4 Hz, 1H), 5.11(dd, J = 10.5, 2.7 Hz, 1H), 4.83-4.75 (m, 1H), 4.07-3.99 (m, 1H),3.51-3.34 (m, 2H), 3.32 (s, 3H), 3.06- 2.78 (m, 4H), 2.74-2.56 (m, 4H),2.46 (t, J = 7.8 Hz, 2H), 2.07-1.94 (m, 6H), 1.63- 1.55 (m, 2H),1.54-1.47 (m, 2H), 1.40 (s, 9H), 1.34-1.28 (m, 4H) F43

tert-butyl 3- [(1r,4r)- 4-[1-(2,6- dioxo- piperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol- 5-yl] cyclohexyl] propanoate 470.25 (300 MHz,CDCl3) δ 8.03 (s, 1H), 7.01- 6.88 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H),5.23 (dd, J = 12.5, 5.4 Hz, 1H), 3.47 (s, 3H), 2.97 (d, J = 16.1 Hz,1H), 2.93-2.66 (m, 2H), 2.62 (s, 1H), 2.28 (t, J = 7.5 Hz, 3H),1.90-1.88 (m, 1H), 1.84-1.71 (m, 3H), 1.68-1.61 (m, 6H), 1.49 (s, 9H),1.30-1.21 (m, 1H) F44

methyl 4-[3- [(2S)- 2-[(tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy]- 2-chloro-5- fluoro phenyl] butanoate 461.25 (300 MHz, DMSO-d₆)δ 7.28 (s, 1H), 6.99 (dd, J = 10.6, 2.9 Hz, 1H), 6.89-6.71 (m, 3H),4.06-3.89 (m, 2H), 3.78 (d, J = 5.2 Hz, 1H), 2.83-2.67 (m, 2H), 2.36-2.30 (m, 2H), 2.16-2.11 (m, 2H), 1.85- 1.80 (m, 3H), 1.69-1.45 (m, 2H),1.39 (s, 9H), 1.40-1.26 (m, 2H) F45

methyl 4-[3- [(2S)- 2-[(tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy]- 2,5-difluoro phenyl] butanoate 445.15 (300 MHz, DMSO-d₆) δ 7.27(s, 1H), 7.03-6.93 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.78-6.65 (m, 2H),3.95 (t, J = 6.0 Hz, 2H), 3.76-3.74 (m, 1H), 3.59 (s, 3H), 2.61-2.55 (m,2H), 2.32-2.27 (m, 2H), 2.11-2.08 (m, 2H), 1.81-1.75 (m, 3H), 1.52-1.47(m, 1H), 1.39 (s, 9H) F46

methyl 4-[3- [(2S)- 2-[(tert- butoxy- carbonyl) amino]-4- carbamoyl-butoxy]- 2-chloro- 5-methyl- phenyl] butanoate 457.20 ¹H NMR (300 MHz,Chloroform-d) δ 6.68 (s, 1H), 6.59 (s, 1H), 6.39 (s, 1H), 5.41 (s, 1H),5.16 (d, J = 8.5 Hz, 1H), 4.06-4.03 (m, 3H), 3.69 (s, 3H), 2.74 (t, J =8.7 Hz, 2H), 2.37 (t, J = 7.3 Hz, 4H), 2.30 (s, 3H), 2.14-2.02 (m, 2H),2.00- 1.91 (m, 2H), 1.47 (s, 9H) F47

tert-butyl N- [(2S,11S)-2- [[(1S)-3- carbamoyl- 1-[[(4- methane-sulfonyl- phenyl) methyl] carbamoyl] propyl] carbamoyl]- 6-[6-[1-(2,6-dioxo- piperidin-3- yl)-3-methyl- 2-oxo-1,3- benzodiazol-5-yl]hexyl]- 12-oxo-1- azatricyclo [6.4.1.0^(∧) [4,13]] trideca-4(13),5,7- trien-11- yl] carbamate 983.20 (300 MHz, DMSO-d₆) δ 11.06 (s,1H), 8.22 (d, J = 9.1 Hz, 1H), 7.84 (t, J = 8.0 Hz, 2H), 7.53-7.41 (m,2H), 7.26-7.24 (m, 1H), 7.03-6.98 (m, 3H), 6.94-6.80 (m, 4H), 6.75 (s,1H), 5.36-5.26 (m, 4H), 5.07-5.05 (m, 1H), 4.39-4.34 (m, 2H), 4.22-4.18(m, 1H), 4.02-3.98 (m, 1H), 3.17-2.96 (m, 4H), 2.70-2.60 (m, 5H),2.10-1.70 (m, 7H), 1.58-1.46 (m, 5H), 1.39 (s, 9H), 1.38-1.32 (m, 8H)

Tert-butylN-[(3S,4R)-1-carbamoyl-4-[(4-[4-[2-([[(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamido]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidin-2-yl]formamido]methyl)-5-(4-methyl-1,3-thiazol-5-yl)phenoxy]butyl]phenyl)methoxy]pentan-3-yl]carbamate.(Intermediate F7)

A mixture of tert-butylN-[(3S,4R)-4-[[4-(4-bromobutyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamate(18.0 mg, 0.038 mmol),(2S,4R)-1-[(2S)-2-[(1-fluorocyclopropyl)formamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[2-hydroxy-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(20.3 mg, 0.038 mmol), K₂CO₃ (10.6 mg, 0.076 mmol) and KI (1.00 mg,0.006 mmol) in DMA (1.00 mL) was stirred for 16 hours at 60° C. undernitrogen atmosphere. The mixture was cooled down to room temperature.The mixture was purified by reversed phase flash chromatography with thefollowing conditions: Column: WelFlash™ C18-I, 20-40 um, 120 g; EluentA: water (plus 10 mmol/LAcOH); Eluent B: ACN; Gradient: 40%-60% B in 20min; Flow rate: 50 mL/min; Detector: UV 220/200 nm; desired fractionswere collected at 56% B to afford the title compound as a white solid(10.0 mg, 28%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.50 (t, J=6.0Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.27-7.22 (m, 6H), 7.05-6.90 (m, 2H),6.69 (s, 1H), 6.61 (d, J=9.1 Hz, 1H), 5.17 (s, 1H), 4.61 (d, J=9.2 Hz,1H), 4.52 (t, J=8.3 Hz, 1H), 4.45 (d, J=12.7 Hz, 2H), 4.39-4.15 (m, 3H),4.07 (s, 2H), 3.64 (q, J=11.0 Hz, 2H), 3.52-3.38 (m, 2H), 2.65 (d, J=6.3Hz, 2H), 2.46 (s, 3H), 2.09-2.04 (m, 4H), 1.94 (d, J=11.4 Hz, 1H), 1.77(s, 5H), 1.38 (s, 11H), 1.23 (d, J=8.1 Hz, 2H), 1.09-1.05 (m, 3H), 0.97(s, 9H); MS (ESI, m/z): [(M+1)]⁺=923.65.

The following intermediates in Table 23 were prepared according to theabove procedure to prepare Intermediate F7.

TABLE 23 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMR F8

tert-butyl N-(3S,4R)- 1-carbamoyl- 4-[(4-[5-[2- ([[(2S,4R)-1-[(2S)-2-[(1- fluorocyclo- propyl) formamido]- 3,3-dimethyl- butanoyl]-4-hydroxy pyrrolidin-2-yl] formamido] methyl)- 5-(4-methyl-1,3-thiazol-5- yl)phenoxy] pentyl]phenyl) methoxy] pentan-3-yl]carbamate  937.6 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.49 (t, J =5.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.32-7.26 (m, 1H), 7.24-7.20 (m,3H), 7.16 (d, J = 7.9 Hz, 2H), 7.00 (d, J = 1.7 Hz, 1H), 6.95 (dd, J =7.8, 1.6 Hz, 1H), 6.67 (s, 1H),6.59 (d, J = 9.1Hz, 1H), 5.17 (s, 1H),4.61 (d, J = 9.1 Hz, 1H), 4.53 (t, J = 8.2 Hz, 1H), 4.43 (d, J = 4.6 Hz,2H), 4.38 (d, J = 10.6 Hz, 1H), 4.29 (dd, J = 16.4, 6.0 Hz, 1H), 4.19(dd, J = 16.6, 5.6 Hz, 1H), 4.05 (t, J = 6.3 Hz, 2H), 3.70-3.59 (m, 2H),3.49-3.38 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.15-2.01 (m,3H), 1.96-1.90 (m, 1H), 1.80- 1.77 (m, 3H), 1.68-1.64 (m, 2H), 1.52-1.47(m, 3H), 1.38 (s, 11H), 1.27-1.19 (m, 2H), 1.06 (d, J = 6.0 Hz, 3H),0.97 (s, 9H). F9

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4-[3-[2- (2-[2-[2-([[(2S,4R)-1- [(2S)-2-[(1- fluorocyclo- propyl) formamido]- 3,3-dimethyl- butanoyl]- 4-hydroxy- pyrrolidin- 2-yl] formamido]methyl)-5-(4- methyl- 1,3-thiazol- 5-yl)phenoxy] ethoxy] ethoxy) ethoxy]propyl] phenyl) methoxy] pentan-3- yl]carbamate  543.6 ¹H NMR (400 MHzDMSO-d₆) δ 8.98 (s, 1H), 8.47 (t, J = 6.0 Hz, 1H), 7.41 (d, J = 7.8 Hz,1H), 7.29 (dd, J = 9.3, 2.7 Hz, 1H), 7.23-7.20 (m, 3H), 7.13 (d, J = 7.8Hz, 2H), 7.04 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 7.8, 1.6 Hz, 1H), 6.67(s, 1H), 6.59 (d, J = 9.1 Hz, 1H), 5.16 (d, J = 3.6 Hz, 1H), 4.60 (d, J= 9.2 Hz, 1H), 4.52 (t, J = 8.2 Hz, 1H), 4.42 (d, J = 3.3 Hz, 2H), 4.36(s, 1H), 4.34-4.27 (m, 1H), 4.26-4.15 (m, 3H), 3.80 (dd, J = 5.7, 3.6Hz, 2H), 3.72-3.60 (m, 3H), 3.60-3.38 (m, 6H), 3.41-3.29 (m, 6H), 2.58(t, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.14-1.98 (m, 2H), 1.98-1.88 (m, 1H),1.82-1.70 (m, 3H), 1.48 (s, 1H), 1.38 (s, 9H), 1.37-1.34 (m, 2H),1.24-1.20 (m, 2H), 1.08-0.99 (m, 3H), 0.96 (s, 9H). F10

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4-[1-[2- ([[(2S,4R)-1-[(2S)-2-[(1- fluorocyclo- propyl) formamido]- 3,3- dimethyl-butanoyl]- 4-hydroxy- pyrrolidin- 2-yl] formamido] methyl)-5-(4- methyl-1,3-thiazol-5- yl)phenoxy]- 3,6,9,12- tetraoxapenta- decan-15-yl]phenyl) methoxy] pentan- 3-yl] carbamate 1086.3 ¹H NMR (400 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.47 (t, J = 5.9 Hz, 1H), 7.41 (d, J = 7.8 Hz,1H), 7.32-7.25 (m, 1H), 7.24-7.19 (m, 3H), 7.13 (d, J = 7.8 Hz, 2H),7.04 (d, J = 1.7 Hz, 1H), 6.97 (dd, J = 7.8, 1.6 Hz, 1H), 6.67 (s, 1H),6.59 (d, J = 9.1 Hz, 1H), 5.16 (d, J = 3.6 Hz, 1H), 4.60 (d, J = 9.2 Hz,1H), 4.52 (t, J = 8.2 Hz, 1H), 4.42 (d, J = 3.4 Hz, 2H), 4.36 (s, 1H),4.33-4.26 (m, 1H), 4.26-4.15 (m, 3H), 3.79 (t, J = 4.7 Hz, 2H), 3.66-3.60 (m, 3H), 3.58-3.33 (m, 15H), 2.58 (t, J = 7.7 Hz, 2H), 2.46 (s,3H), 2.13-1.98 (m, 3H), 1.98-1.89 (m, 1H), 1.83-1.72 (m, 3H), 1.48 (t, J= 7.1 Hz, 1H), 1.38 (s, 11H), 1.26-1.18 (m, 2H), 1.05 (d, J = 6.0 Hz,3H), 0.96 (s, 9H). F11

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4-[1-[2- ([[(2S,4R)-1-[(2S)-2-[(1- fluorocyclo- propyl) formamido]- 3,3-dimethyl- butanoyl]-4-hydroxy- pyrrolidin- 2-yl] formamido] methyl)-5-(4- methyl-1,3-thiazol-5- yl)phenoxy]- 3,6,9,12,15-n pentaoxaocta- decan-18-yl] phenyl)methoxy] pentan-3- yl] carbamate 1129.8 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98(s, 1H), 8.48 (t, J = 6.0 Hz, 1H), 7.67-7.54 (m, 1H), 7.41 (d, J = 7.8Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.25-7.21 (m, 3H), 7.14 (d, J = 7.8Hz, 2H), 7.04 (d, J = 1.7 Hz, 1H), 6.97 (dd, J = 7.8, 1.6 Hz, 1H), 6.67(s, 1H), 6.59 (d, J = 9.0 Hz, 1H), 5.16 (d, J = 3.7 Hz, 1H), 4.60 (d, J= 9.2 Hz, 1H), 4.56-4.44 (m, 1H), 4.42 (d, J = 3.3 Hz, 2H), 4.36 (s,2H), 4.34- 4.26 (m, 1H), 4.26-4.15 (m, 3H), 3.79 (dd, J = 5.7, 3.5 Hz,2H), 3.68- 3.44 (m, 8H), 3.43-3.36 (m, 1H), 3.34 (d, J = 18.8 Hz, 6H),2.58 (t, J =7.6 Hz, 3H), 2.46 (s, 4H), 2.14- 1.88 (m, 2H), 1.80-1.72 (m,4H), 1.48 (s, 1H), 1.38 (s, 10H), 1.35 (d, J = 8.3 Hz, 2H), 1.26-1.19(m, 3H), 1.08-0.99 (m, 5H), 0.96 (s, 9H). F12

tert-butyl N- [(3S,4R)-1- carbamoyl- 4-[(4-[3-[2- ([[(2S,4R)-1-[(2S)-2-[(1- fluorocyclo- propyl) formamidol- 3,3-dimethyl-butanoyl]-4- hydroxy- pyrrolidin- 2-yl] formamidol] methyl)-5-(4-methyl- 1,3-thiazol-5- yl)phenoxy] propyl] phenyl) methoxy] pentan-3-yl] carbamate  909.6 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.51 (t,J = 6.0 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.33-7.17 (m, 6H), 6.97 (s,2H), 7.01-6.93 (m, 1H), 6.68 (s, 1H), 6.60 (d, J = 9.1 Hz, 1H), 5.17 (d,J = 3.6 Hz, 1H), 4.61 (d, J = 9.2 Hz, 1H), 4.53 (t, J = 8.2 Hz, 1H),4.49-4.38 (m, 2H), 4.36 (s, 1H), 4.37-4.21 (m, 2H), 4.05 (t, J = 6.0 Hz,2H), 3.70-3.57 (m, 2H), 3.43-3.36 (m, 1H), 3.33 (s, 1H), 2.82-2.74 (m,2H), 2.45 (s, 3H), 2.14-2.01 (m, 5H), 2.03-1.88 (m, 1H), 1.51- 1.39 (m,1H), 1.37 (s, 8H), 1.36-1.32 (m, 2H), 1.23 (dd, J = 8.5, 3.3 Hz, 2H),1.08-0.99 (m, 4H), 0.97 (s, 9H). F13

tert-butyl N- [(3S,4R)-1- carbamoyl-4- [[4-(3-[2-[2- ([[(2S,4R)-1-[(2S)-2-[(1- flourocyclo- propyl) formamido]- 3,3- dimethyl- butanoyl]-4-hydroxy- pyrrolidin-2- yl]formamido] methyl)-5-(4- methyl-1,3-thiazol-5- yl)phenoxy] ethoxy] propyl) phenyl] methoxy] pentan-3-yl] carbamate  953.5 ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 7.36 (d, J= 7.6 Hz, 1H), 7.32 (d, J = 5.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.16(d, J = 7.8 Hz, 2H), 7.07 (dd, J = 9.0, 3.4 Hz, 1H), 6.99 (dd, J =7.7,1.5 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.39 (s, 1H), 5.51 (s, 1H), 4.95(d, J = 9.7 Hz, 1H), 4.67 (t, J = 7.8 Hz, 1H), 4.61-4.54 (m, 2H), 4.51(q, J = 6.2, 5.6 Hz, 2H), 4.47- 4.35 (m, 2H), 4.22 (q, J = 5.2 Hz, 2H),3.95 (d, J = 11.0 Hz, 1H), 3.90- 3.82 (m, 2H), 3.66 (dd, J = 11.1,3.9Hz, 2H), 3.60-3.54 (m, 4H), 2.71 (t, J = 7.5 Hz, 2H), 2.55 (s, 3H), 2.42(dt, J = 13.0, 6.9 Hz, 1H), 2.27 (d, J = 9.5 Hz, 2H), 1.99-1.91 (m, 4H),1.75-1.67 (m, 1H), 1.45 (s, 9H), 1.36-1.22 (m, 4H), 1.22 (d, J = 6.2 Hz,3H), 0.96 (s, 9H). F14

tert-butyl N- [(3S,4R)-1- carbamoyl-4- [[4-[3-[2- [2-[2- ([[(2S,4R)-1-[(2S)-2-[(1- fluorocyclo- propyl) formamido]- 3,3-dimethyl- butanoyl]-4-hydroxy- pyrrolidin- 2-yl] formamido] methyl)-5-(4- methyl-1,3-thiazol-5- yl)phenoxy] ethoxy] ethoxy) propyl] phenyl] methoxy)pentan-3- yl]carbamate  997.7 ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1H),7.36 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 5.8 Hz, 1H), 7.22 (d, J = 7.8 Hz,2H), 7.16 (d, J = 7.8 Hz, 2H), 7.07 (dd, J = 9.0, 3.4 Hz, 1H), 6.99 (dd,J =7.7 , 1.5 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.39 (s, 1H), 5.51 (s,1H), 4.95 (d, J = 9.7 Hz, 1H), 4.67 (t, J = 7.8 Hz, 1H), 4.61-4.54 (m,2H), 4.51 (q, J = 6.2, 5.6 Hz, 2H), 4.47- 4.35 (m, 2H), 4.22 (q, J = 5.2Hz, 2H), 3.95 (d, J = 11.0 Hz, 1H), 3.90- 3.82 (m, 2H), 3.66 (dd, J =11.1, 3.9 Hz, 2H), 3.60-3.54 (m, 8H), 2.71 (t, J = 7.5 Hz, 2H), 2.55 (s,3H), 2.42 (dt, J = 13.0, 6.9 Hz, 1H), 2.27 (d, J = 9.5 Hz, 2H),1.99-1.91 (m, 4H), 1.75-1.67 (m, 1H), 1.45 (s, 9H), 1.36-1.22 (m, 4H),1.22 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H).

(9H-fluoren-9-yl)methyl((3S,6S)-6-(((2R,3S)-6-amino-2-((4-(16-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-5-oxo-7,10,13-trioxa-4-azahexadecyl)benzyl)oxy)-6-oxohexan-3-yl)carbamoyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-yl)carbamate(Intermediate G)

Step 1. Tert-butyl 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)acetate. Asolution of 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethan-1-ol (7.50 g, 52.0mmol) in THF (100 mL) was treated with NaH (2.70 g, 67.6 mmol, 60%dispersion in mineral oil) at 0° C. for 1 hour under nitrogenatmosphere. Followed by the addition of a solution of tert-butyl2-bromoacetate (12.2 g, 62.4 mmol) in THF (50.0 mL) dropwise at 0° C.The resulting mixture was stirred for 16 hours at room temperature undernitrogen atmosphere and quenched with saturated aqueous NH₄Cl solution(200 mL) at 0° C. The resulting mixture was extracted with ethyl acetate(2×200 mL). The combined organic layers was washed with brine (300 mL)and dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with 10% ethyl acetate in petroleumether to afford the title compound as a light yellow oil (2.70 g, 20%):¹H NMR (400 MHz, CDCl₃) δ 4.21 (d, J=2.4 Hz, 2H), 4.03 (s, 2H),3.74-3.62 (m, 8H), 2.43 (t, J=2.4 Hz, 1H), 1.48 (s, 9H).

The following intermediates in Table 24 were prepared according to Step1 to prepare Intermediate G.

TABLE 24 Characterization data for intermediates prepared according toprocedure above. Inter- medi- Chemical ate Structure Name ¹H-NMR G-1-1

tert-butyl 3,6,9,12- tetraoxa- pentadec-14- yn-1-oate ¹H NMR (400 MHz,CDCl₃) 4.21 (d, J = 2.4 Hz, 2H), 4.03 (s, 2H), 3.75-3.61 (m, 8H), 2.43(t, J = 2.4 Hz, 1H), 1.48 (s, 9H). G-1-2

tert-butyl 2- [2-(prop-2- yn-1- yloxy) ethoxy] acetate ¹H NMR (400 MHz,CDCl₃) δ 4.23 (d, J = 2.3 Hz, 2H), 4.03 (d, J = 1.3 Hz, 2H), 3.75 (s,4H), 2.43 (t, J = 2.4 Hz, 1H), 1.48 (s, 9H). G-1-3

tert-butyl 2- (prop-2-yn- 1-yloxy) acetate ¹H NMR (400 MHz, CDCl₃) δ4.32 (d, J = 2.4 Hz, 2H), 4.09 (s, 2H), 2.48 (t, J = 2.4 Hz, 1H), 1.50(s, 9H).

Step 2. tert-Butyl2-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)acetate.The titled compound was prepared according to Step 2 and 3 to prepareIntermediate B. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.35 (d,J=1.5 Hz, 1H), 7.24-7.09 (m, 2H), 5.40 (dd, J=12.7, 5.3 Hz, 1H), 4.40(d, J=3.3 Hz, 2H), 4.15 (d, J=2.4 Hz, 1H), 4.01-3.97 (m, 3H), 3.64 (tt,J=3.6, 1.8 Hz, 2H), 3.35 (s, 2H), 3.01-2.81 (m, 1H), 2.79-2.57 (m, 2H),2.11-2.00 (m, 2H), 1.43 (s, 4H), 1.42 (s, 9H); MS (ESI, m/z):[(M+1)]⁺=514.3.

The following intermediates in Table 25 below were prepared accordingStep 2 to prepare Intermediate G above using the different bromides (1equiv.) and terminal alkynes (4-5 equiv.).

TABLE 25 Characterization data for intermediates prepared according toprocedure above. Chemical MS: Intermediate Structure Name [(M + 1)]⁺¹H-NMR G-2-2

tert-butyl 15- [1-(2,6- dioxopiperidin- 3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5-yl]- 3,6,9,12- tetraoxapentadec- 14-ynoate[(M + 18)]⁺ = 577.4 (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.35 (d, J = 1.4Hz, 1H), 7.21- 7.12 (m, 2H), 5.40 (dd, J = 12.6, 5.4 Hz, 1H), 4.40 (s,2H), 3.99 (d, J = 1.3 Hz, 3H), 3.71-3.56 (m, 12H), 3.55 (s, 2H),1.79-1.74 (m, 4H), 1.42 (s, 9H). G-2-3

tert-butyl 2- [2-[2-([3- [3-methyl-1- (1-methyl-2,6- dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]prop-2-yn-1- yl]oxy)ethoxy]ethoxy]acetate [(M + 23)]⁺ = 552.3 (400 MHz, DMSO-d₆) δ 7.35 (d, J = 3.1Hz, 1H), 7.16 (d, J = 2.7 Hz, 2H), 5.46 (dd, J = 12.7, 4.3 Hz, 1H ),4.40 (d, J = 2.8 Hz, 2H), 3.99 (d, J = 2.8 Hz, 2H), 3.68-3.51 (m, 8H),3.35 (d, J = 2.8 Hz, 3H), 3.04 (d, J = 2.6 Hz, 3H), 2.96 (d, J = 15.2Hz, 1H), 2.78 (d, J = 17.7 Hz, 1H), 2.71 (d, J = 13.4 Hz, 1H), 2.08 (t,J = 2.2 Hz, 1H), 1.42 (d, J = 3.0 Hz, 9H). G-2-4

tert-butyl 2- [2-([3-[1-(2,6- dioxopiperidin- 3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]prop- 2-yn-1-yl]oxy) ethoxy]acetate470.2 (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.35 (d, J = 1.5 Hz, 1H),7.25- 7.10 (m, 2H), 5.40 (dd, J = 12.7, 5.4 Hz, 1H), 4.41 (d, J = 2.1Hz, 2H), 4.00 (d, J = 10.4 Hz, 2H), 3.68-3.63 (m, 4H), 3.35 (s, 3H),3.00-2.81 (m, 1H), 2.81-2.59 (m, 2H), 2.07-1.98 (m, 1H), 1.43 (d, J =2.2 Hz, 9H). G-2-5

tert-butyl 2- [2-([3-[3-methyl- 1-(1-methyl-2,6- dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]prop 2- yn-1-yl]oxy) ethoxy]acetate[(M + 18)]⁺ = 503.3 (400 MHz, DMSO-d₆) δ 7.35 (s, 1H), 7.16 (s, 2H),5.46 (dd, J = 13.1, 5.3 Hz, 1H), 4.41 (s, 2H), 4.01 (s, 2H), 3.66-3.64(m, 4H), 3.36 (s, 3 H), 3.04 (s, 3H), 3.01-2.92 (m, 1H), 2.83-2.65 (m,2H), 2.15-1.90 (m, 1 H), 1.43 (s, 9H). G-2-6

tert-butyl 2- ([3-[1-(2,6- dioxopiperidin- 3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]prop-2-yn-1- yl]oxy)acetate 428.2 (400MHz, DMSO-d₆) δ 11.14 (s, 1H), 7.36 (d, J = 1.4 Hz, 1H), 7.22- 7.12 (m,2H), 5.40 (dd,J = 12.7, 5.4 Hz, 1H), 4.47 (s, 2H), 4.11 (s, 2H), 3.35(s, 3H), 2.96-2.83 (m, 1H), 2.78-2.60 (m, 2H), 2.07-2.00 (m, 1H), 1.44(s, 9H). G-2-7

tert-butyl 2-([3-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy] methyl)phenyl] prop-2-yn-1-yl] oxy)acetate505.4 (400 MHz, DMSO-d₆) δ 7.42 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 7.9Hz, 2H), 7.22 (s, 1H), 6.71-6.59 (m, 2H), 5.76 (d, J = 1.3 Hz, 1H),4.54- 4.44 (m, 4H), 4.09 (s, 2H), 3.52- 3.36 (m, 2H), 2.14-1.96 (m, 2H),1.78 (d, J = 9.8 Hz, 1H), 1.43 (d, J =1.2 Hz, 9H), 1.38 (s, 9H), 1.07(d, J = 6.0 Hz, 3H). G-2-8

tert-butyl 2-([4-[4- ([[(2R,3S)- 3-[4(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy]methyl) phenyl]but-3- yn-1-yl]oxy) acetate519.4 (400 MHz, DMSO-d₆) δ 7.36-7.28 (m, 4H), 7.22 (s, 1H), 6.71-6.59(m, 2H), 4.47 (t, J = 2.8 Hz, 2H), 4.04 (d, J = 3.0 Hz, 2H), 3.64 (td, J= 6.8, 2.6 Hz, 2H), 3.40 (d, J = 6.1 Hz, 2H), 2.68 (td, J = 6.8, 2.7 Hz,2H), 2.14-1.96 (m, 2H), 1.78 (s, 1H), 1.48 (s, 1H), 1.43 (d, J = 2.9 Hz,9H), 1.38 (d, J = 2.7 Hz, 9H), 1.06 (dd, J = 6.1, 2.6 Hz, 3H). G-2-9

tert-butyl 5-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-carbamoyl pentan-2-yl]oxy] methyl)phenyl] pent-4-ynoate 489.3 (400 MHz,CD₃OD) δ 7.32 (d, J = 1.5 Hz, 4H), 4.62-4.46 (m, 2H), 3.63-3.46 (m, 2H),2.67 (t, J = 7.3 Hz, 2H), 2.56-2.48 (m, 2H), 2.35- 2.17 (m, 2H), 1.98(ddt, J = 13.5, 10.0, 4.8 Hz, 1H), 1.70-1.57 (m, 1H), 1.49 (s, 9H), 1.45(s, 9H), 1.18 (d, J = 6.2 Hz, 3H). G-2-10

tert-butyl 2- [2-([3-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy] methyl)phenyl] prop-2-yn-1- yl]oxy)ethoxy]acetate 549.4 (400 MHz, DMSO-d₆) 7.41 (d, J = 8.0 Hz, 2H), 7.34 (d, J =8.0 Hz, 2H), 7.21 (s, 1H), 6.72-6.58 (m, 2H), 4.56-4.45 (m, 2H), 4.40(s, 2H), 4.01 (s, 2H), 3.62-3.55 (m, 1H), 3.44 (dt, J = 11.7, 7.2 Hz,2H), 2.08-1.96 (m, 2H), 1.85-1.71 (m, 1H), 1.43 (s, 9H), 1.38 (s, 9H),1.07 (d, J = 6.0 Hz, 3H). G-2-11

tert-butyl 2- [2-[2-([3- 4-([[(2R,3S)- 3-[(tert- butoxycarbonyl)amino]-5- carbamoylpentan- 2-yl]oxy] methyl)phenyl] prop-2-yn-l-yl]oxy)ethoxy] ethoxy]acetate 593.4 (400 MHz, DMSO-d₆) δ 7.41 (d, J =8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 6.71-6.59 (m, 2H),4.55-4.44 (m, 2H), 4.40 (s, 2H), 3.99 (s, 2H), 3.64 (dd, J = 6.3, 3.6Hz, 2H), 3.63-3.54 (m, 4H), 3.55 (t, J = 5.2 Hz, 3H), 3.49-3.37 (m, 2H),2.07-1.93 (m, 1H), 1.84- 1.73 (m, 1H), 1.43 (d, J = 2.5 Hz, 9H), 1.38(s, 9H), 1.07 (d, J = 6.0 Hz, 3H). G-2-12

tert-butyl 15-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy] methyl)phenyl]- 3,6,9,12-tetraoxa-pentadec-14- ynoate 637.4 (400 MHz, DMSO-d₆) δ 7.41 (d, J = 8.0 Hz, 2H),7.37-7.27 (m, 2H), 7.21 (s, 1H), 6.68 (s, 1H), 6.63 (d, J = 9.0 Hz, 1H),4.55-4.43 (m, 2H), 4.39 (d, J = 3.4 Hz, 2H), 3.98 (d, J = 3.4 Hz, 2H),3.67-3.56 (m, 3H), 3.60-3.35 (m, 9H), 2.16-1.95 (m, 3H), 1.78 (s, 1H),1.49 (s, 1H), 1.45-1.35 (m, 18H), 1.10-1.04 (m, 3H). G-2-16

methyl 5-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-(methylcarbamoyl) pentan-2- yl]oxy]methyl) phenyl]pent- 4-ynoate 461.3(400 MHz, DMSO-d₆) δ 7.67 (d, J = 5.0 Hz, 1H), 7.35-7.26 (m, 4H), 6.61(d, J = 9.1 Hz, 1H), 4.53-4.41 (m, 2H), 3.64 (s, 3H), 3.62 (s, 3H),3.49-3.35 (m, 1H), 2.72-2.57 (m, 4H), 2.55-2.51 (m, 2H), 2.12-1.98 (m,1H), 1.78 (dtd, J = 13.2, 9.1, 5.5 Hz, 1H), 1.49 (dt, J = 14.0, 4.7 Hz,1H), 1.38 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H). G-2-17

methyl 6-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy] methyl)phenyl] hex-5-ynoate 461.2 (400 MHz,DMSO-d₆) δ 7.36-7.30 (m, 4H), 7.23 (s, 1H), 6.69 (s, 1H), 6.63 (d, J =9.1 Hz, 1H), 4.49 (t, J = 8.0 Hz, 2H), 3.61 (s, 3H), 3.48-3.37 (m, 1H),2.50-2.40 (m, 2H), 2.37 (dt, J = 18.0, 7.1 Hz, 2H), 2.04 (td, J = 14.8,8.4 Hz, 2H), 1.85-1.70 (m, 4H), 1.50-1.40 (m, 1H), 1.38 (s, 9H), 1.07(d, J = 6.1 Hz, 3H). G-2-18

methyl 5-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy] methyl)phenyl] pent-4-ynoate 447.4 (400 MHz,CDCl₃) δ 7.42-7.35 (m, 2H), 7.27-7.22 (m, 2H), 6.49 (s, 1H), 6.05 (s,1H), 4.85 (d, J = 9.7 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.40 (d, J =12.0 Hz, 1H), 3.74 (s, 3H), 3.72-3.55 (m, 2H), 2.75 (ddd, J = 8.3, 6.7,1.5 Hz, 2H), 2.66 (ddd, J = 8.2, 6.8, 1.5 Hz, 2H), 2.37-2.22 (m, 2H),1.97 (td, J = 12.8, 11.2, 5.6 Hz, 1H), 1.70 (ddd, J = 20.3, 12.1, 6.0Hz, 1H), 1.45 (s, 9H), 1.20 (d, J = 6.3 Hz, 3H). G-2-19

methyl 5-[3- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy] methyl)phenyl] pent-4-ynoate 447.3 (400 MHz,CD₃OD) δ 7.38 (d, J = 1.7 Hz, 1H), 7.35-7.25 (m, 3H), 4.55 (d, J = 11.7Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 3.72 (s, 3H), 3.61 (ddd, J = 10.8,5.2, 3.2 Hz, 1H), 3.57-3.49 (m, 1H), 2.76-2.69 (m, 2H), 2.69-2.60 (m,2H), 2.36-2.17 (m, 2H), 1.97 (dddd, J = 12.9, 9.6, 6.7, 3.2 Hz, 1H),1.70-1.55 (m, 1H), 1.46 (s, 9H), 1.18 (d, J = 6.2 Hz, 3H). G-2-20

methyl 6-[2- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy] methyl)phenyl] hex-5-ynoate 461.2 (400 MHz,DMSO-d₆) δ 7.66-7.18 (m, 5H), 6.73-6.59 (m, 2H), 4.69- 4.49 (m, 2H),3.61 (s, 3H), 3.55- 3.40 (m, 2H), 2.43-2.30 (m, 6H), 2.05 (ddt, J =15.0, 10.0, 5.2 Hz, 1H), 1.83 (p, J = 7.2 Hz, 1H), 1.72 (p, J = 7.1 Hz,2H), 1.39 (s, 9H), 1.11 (t, J = 5.3 Hz, 3H). G-2-21

6-[1-(2,6- dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3- benzodiazol-5-yl]hex- 5-ynoic acid 370.1 (400 MHz, DMSO-d₆) δ 12.11 (br, 1H), 11.12(s, 1H), 7.26 (d, J = 1.1 Hz, 1H), 7.10 (m, 2H), 5.38 (dd, J = 12.7, 5.4Hz, 1H), 3.34 (s, 3H), 2.98-2.83 (m, 1H), 2.78-2.58 (m, 2H), 2.46 (t, J= 7.1 Hz, 2H), 2.39 (q, J = 5.9, 4.5 Hz, 1H), 2.36-2.14 (m, 1H),2.08-1.98 (m, 1H), 1.78 (p, J = 7.2 Hz, 2H). G-2-22

7-[1-(2,6- dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3- benzodiazol-5-yl]hept-6-ynoic acid 384.1 (400 MHz, DMSO-d₆) δ 12.09 (br, 1H), 11.11 (s,1H), 7.24 (d, J = 1.4 Hz, 1H), 7.18-6.97 (m, 2H), 5.43 (dd, J = 12.7,5.3 Hz, 1H), 3.37 (s, 3H), 3.03-2.83 (m, 1H), 2.79-2.56 (m, 2H), 2.43(t, J = 6.9 Hz, 2H), 2.28 (t, J = 7.2 Hz, 2H), 2.07-1.98 (m, 1H), 1.65(ddd, J = 11.8, 8.7, 5.7 Hz, 2H), 1.56 (dq, J = 8.2, 6.4, 5.9 Hz, 2H).G-2-23

8-[1-(2,6- dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3- benzodiazol-5-yl]oct-7- ynoic acid 398.2 (400 MHz, DMSO-d₆) δ 12.00 (br, 1H), 11.13(s, 1H), 7.24 (s, 1H), 7.09 (s, 2H), 5.38 (dd, J = 12.9, 5.2 Hz, 1H),3.33 (s, 3H), 2.89 (t, J = 16.8 Hz, 1H), 2.67 (m, 2H), 2.42 (t, J = 7.0Hz, 2H), 2.23 (t, J = 7.3 Hz, 2H), 2.10-2.00 (m, 1H), 1.55 (m, 4H), 1.43(q, J = 7.6 Hz, 2H). G-2-24

8-[1-(2,6- dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3- benzodiazol-4-yl]oct-7- ynoic acid 398.2 (400 MHz, DMSO-d₆) δ 12.02 (br, 1H), 11.13(s, 1H), 7.12 (dd, J = 7.7, 1.3 Hz, 1H), 7.06 (dd, J = 7.9, 1.2 Hz, 1H),6.99 (t, J = 7.8 Hz, 1H), 5.39 (dd, J = 12.7, 5.4 Hz, 1H), 3.64 (s, 3H),2.98-2.82 (m, 1H), 2.79- 2.56 (m, 2H), 2.24 (t, J = 7.1 Hz, 2H), 2.18(dd, J = 9.4, 7.3 Hz, 1H), 2.02 (ddd, J = 10.8, 5.8, 3.6 Hz, 1H),1.63-1.37 (m, 6H), 1.37-1.19 (m, 1H). G-2-25

8-[2-(2,6- dioxopiperidin- 3-yl)-1- oxo-3H- isoindo1-4- yl]oct-7- ynoicacid 383.2 (400 MHz, DMSO-d₆) δ 11.99 (br, 1H), 10.99 (s, 1H), 7.71 (dd,J = 7.6, 1.1 Hz, 1H), 7.64 (dd, J = 7.7, 1.1 Hz, 1H), 7.57-7.48 (m, 1H),5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 17.7 Hz, 1H), 4.31 (d, J =17.7 Hz, 1H), 2.91 (ddd, J = 17.9, 13.6, 5.5 Hz, 1H), 2.60 (d, J = 17.4Hz, 2H), 2.48 (d, J = 6.9 Hz, 2H), 2.23 (t, J = 7.2 Hz, 2H), 2.09-1.97(m, 1H), 1.57 (m, 4H), 1.45 (td, J = 8.3, 4.3 Hz, 2H). G-2-26

5-[1-(2,6- dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3- benzodiazol-4-yl]pent- 4-ynoic acid 356.1 (400 MHz, DMSO-d₆) δ 12.14 (br, 1H), 11.11(s, 1H), 7.08-7.00 (m, 2H), 6.95 (dd, J = 6.9, 2.1 Hz, 1H), 5.38 (dd, J= 12.6, 5.4 Hz, 1H), 3.52 (s, 3H), 2.98 (ddd, J = 8.5, 7.0, 2.2 Hz, 2H),2.90 (ddd, J = 16.6, 13.2, 5.3 Hz, 1H), 2.78-2.53 (m, 4H), 2.02 (ddt, J= 11.1, 8.8, 2.3 Hz, 1H). G-2-27

7-[3-(2,6- dioxopiperidin- 3-yl)-1-methyl- 2-oxo-1,3- benzodiazol-5-yl]hept- 6-ynoic acid 384.05 (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 11.10(s, 1H), 7.22 (s, 1H), 7.20-7.10 (m, 2H), 5.39 (dd, J = 12.7, 5.3 Hz,1H), 3.34 (s, 3H), 2.94-2.81 (m, 1H), 2.79-2.69 (m, 1H), 2.67-2.58 (m,1H), 2.42 (t, J = 6.9 Hz, 2H), 2.35-2.20 (m, 1H), 2.05-1.97 (m, 1H),1.69-1.61 (m, 2H), 1.57-1.53 (m, 2H) G-2-28

methyl 5-(4- [[(2S)-2- [(tert- butoxycarbonyl) amino]-4-carbamoylbutoxy] methyl] phenyl)pent- 4-ynoate 433.20 (400 MHz, DMSO-d₆)δ 7.38-7.35 (m, 2H), 7.32-7.28 (m, 2H), 6.84- 6.82 (d, J = 8.6 Hz, 1H),6.73-6.68 (m, 2H), 4.46 (s, 2H), 3.95-3.93 (m, 1H), 3.64 (s, 3H),3.61-3.52 (m, 2H), 3.32 (s, 2H), 2.74-2.57 (m, 6H), 2.08-2.04 (m, 2H),1.37 (s, 9H) G-2-29

5-(4-[[(tert- butoxycarbonyl) amino]methyl] phenyl)pent- 4-ynoic acid304.15 (400 MHz, DMSO-d₆) δ 7.23 (q, J = 8.1 Hz, 4H), 6.25 (t, J = 2.3Hz, 1H), 4.11 (d, J = 6.1 Hz, 2H), 3.19- 3.10 (m, 2H), 2.83-2.72 (m,2H), 1.40 (s, 9H) G-2-30

tert-butyl 3-(2[2-[1- (2,6-dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3-benzodiazol- 5-yl]ethynyl] phenyl) propanoate 488.15 (400 MHz, DMSO-d₆)δ 11.14 (s, 1H), 7.51 (dd, J = 7.3, 1.3 Hz, 1H), 7.41 (d, J = 1.5 Hz,1H), 7.36-7.32 (m, 2H), 7.30-7.25 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H),5.45-5.41 (m, 1H), 3.38 (s, 3H), 3.08 (t, J = 7.7 Hz, 2H), 2.96-2.85 (m,1H), 2.77-2.73 (m, 1H), 2.68-2.66 (m, 1H), 2.64- 2.61 (m, 2H), 2.10-2.01(m, 1H), 1.60-1.44 (m, 2H), 1.38 (s, 9H) G-2-31

6-[4-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoyl- butoxy]phenyl]hex-5-ynoic acid 419.15 (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 7.34-7.28(m, 2H), 7.26 (s, 1H), 6.93-6.87 (m, 2H), 6.84 (d, J = 8.5 Hz, 1H), 6.73(s, 1H), 3.90-3.81 (m, 2H), 3.71 (dq, J = 9.1, 4.7 Hz, 1H), 2.46-2.42(m, 4H), 2.21- 2.05 (m, 3H), 1.76 (h, J = 7.2, 6.7 Hz, 2H), 1.64-1.61(m, 1H), 1.39 (s, 9H) G-2-32

6-[3-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoyl- butoxy]phenyl]hex-5-ynoic acid [(M − 1)]⁻ = 417.23 400 MHz, DMSO-d₆) δ 7.25 (t, J =7.6 Hz, 2H), 6.97 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 7.5 Hz, 2H), 6.82(d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 3.92-3.86 (m, 3H), 3.75- 3.67 (m,1H), 3.38 (s, 1H), 2.46 (s, 2H), 2.18-2.04 (m, 3H), 1.84-1.75 (m, 3H),1.64-1.58 (m, 1H), 1.40 (s, 9H) G-2-33

methyl 3-(4-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4-carbamoylbutoxy] prop-1-yn-1- yl]phenyl) propanoate 432.52 (400 MHz,CDCl₃) 7.38 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H),5.49 (s, 1H), 5.02 (d, J = 9.0 Hz, 1H), 4.38 (s, 2H), 3.91-3.77 (m, 1H),3.68 (s, 3H), 3.66-3.60 (m, 2H), 2.96 (t, J = 8.7, 2H), 2.64 (t, J = 8.2Hz, 2H), 2.35- 2.29 (m, 2H), 1.96-1.87 (m, 2H), 1.45 (s, 9H) G-2-34

7-[3-methyl-1-(1- methyl-2,6- dioxopiperidin- 3-yl)-2-oxo-1,3-benzodiazol-5- yl]hept- 6-ynoic acid 398.05 (400 MHz, CDCl₃) δ 7.18-7.13(m, 1H), 7.09 (d, J = 1.5 Hz, 1H), 6.71 12.6, 4.9 Hz, 1H), 3.44 (s, 3H),3.26 (s, 3H), 3.11-3.00 (m, 1H), 2.94- 2.80 (m, 1H), 2.79-2.64 (m, 1H),2.47 (q, J = 6.8 Hz, 4H), 2.40 (dd, J = 13.0, 6.7 Hz, 1H), 2.27-2.09 (m,1H), 1.90-1.78 (m, 2H), 1.74-1.70 (m, 2H) G-2-35

5-(3-[[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoyl- butanamido]methyl] phenyl)pent- 4-ynoic acid 432.20 (400 MHz, DMSO-d₆) δ 8.32 (t, J= 6.1 Hz, 1H), 7.33-.22 (m, 2H), 7.16 (d, J = 9.4 Hz, 2H), 7.13-7.05 (m,2H), 6.94-6.90 (m, 1H), 6.76 (s, 1H), 6.24 (t, J = 2.3 Hz, 1H), 4.29-4.26 (m, 2H), 3.96-.86 (m, 1H), 3.18-3.13 (m, 2H), 2.84 -2.75 (m, 1H),2.19 -2.03 (m, 2H), 1.95-1.79 (m, 1H), 1.76-1.69 (m, 1H), 1.39 (s, 9H)G-2-36

methyl 5-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoyl-pentan-2-yl]oxy] methyl)-2- fluorophenyl] pent-4-ynoate 464.534 (400MHz, DMSO-d₆) δ 7.38 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 9.8 Hz, 2H), 7.13(dd, J = 7.9, 1.5 Hz, 1H), 6.71-6.62 (m, 2H), 4.55-4.43 (m, 2H), 3.64(s, 3H), 3.49 (d, J = 12.4 Hz, 1H), 3.44-3.40 (m, 1H), 2.72 (dd, J =7.6, 5.7 Hz, 2H), 2.65-2.61 (m, 2H), 2.15-1.95 (m, 2H), 1.78- 1.74 (m,1H), 1.54-1.43 (m, 1H), 1.38 (s, 9H), 1.07 (d, J = 6.1 Hz, 3H) G-2-37

methyl 5-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoyl-pentan-2-yl] oxylmethyl)-3- fluorophenyl] pent-4-ynoate 465.20 (400 MHz,DMSO-d₆) δ 7.43 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 8.2 Hz, 3H), 6.68 (s,1H), 6.61 (d, J = 8.9 Hz, 1H), 4.52 (q, J = 12.4 Hz, 2H), 3.64 (s, 3H),3.46-3.41 (m, 2H), 2.72-2.59 (m, 4H), 2.13-1.97 (m, 2H), 1.82-1.69 (m,1H), 1.51-1.42 (m, 1H), 1.38 (s, 9H), 1.07 (d, J = 5.7 Hz, 3H). G-2-38

8-[2-(1-methyl-2,6- dioxopiperidin- 3-yl)-1-oxo- 3H-isoindo1-4-yl]oct-7- ynoic acid 397.20 (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 7.72 (d,J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H),5.22 (dd, J = 13.5, 5.1 Hz, 1H), 4.51-4.27 (m, 2H), 3.07-2.94 (m, 4H),2.78-2.75 (m, 1H), 2.50- 2.40 (m, 3H), 2.23 (t, J = 7.2 Hz, 2H),2.06-2.20 (m, 1H), 1.58-1.54 (m, 4H), 1.46-1.43 (m, 2H). G-2-39

6-[1-[2,6- dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3- benzodiazol-4-yl]hex- 5-ynoic acid 370.00 (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 11.11(s, 1H), 7.16-7.10 (m, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 7.9Hz, 1H), 5.39 (dd, J = 12.6, 5.3 Hz, 1H), 3.64 (s, 3H), 2.40 (t, J = 7.2Hz, 2H), 2.36-2.28 (m, 4H), 2.24-2.14 (m, 2H), 1.86-1.78 (m, 2H) G-2-40

7-[1-(2,6- dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3- benzodiazol-4-yl]hept- 6-ynoic acid 384.15 (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 11.13(d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.7, 1H), 7.06 (d, J = 7.9, 1H), 6.99(dd, J = 7.9, 7.7 Hz, 1H), 5.40 (dd, J = 12.5, 5.4 Hz, 1H), 3.64 (s,3H), 2.96-2.83 (m, 1H), 2.79- 2.59 (m, 3H), 2.54-2.52 (m, 2H), 2.38-2.24(m, 2H), 1.67 (d, J = 7.3 Hz, 1H), 1.62 (d, J = 6.8 Hz, 1H), 1.60-1.56(m, 1H), 1.47 (d, J = 7.9 Hz, 1H) G-2-41

9-[1-(2,6- dioxopiperidin- 3-yl)-3- methyl-2-oxo- 1,3-benzodiazol-4-yl]non- 8-ynoic acid 412.25 (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 11.13(s, 1H), 7.12 (dd, J = 7.8, 1.3 Hz, 1H), 7.06 (dd, J = 7.8, 1.2 Hz, 1H),6.99 (t, J = 7.8 Hz, 1H), 5.39 (dd, J = 12.6, 5.4 Hz, 1H), 3.64 (s, 3H),2.76-2.67 (m, 1H), 2.64- 2.58 (m, 1H), 2.26-2.18 (m, 2H), 1.67-1.47 (m,6H), 1.45-1.21 (m, 6H) G-2-42

6-[3-R2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluorophenyl] hex-5-ynoic acid 436 48 (400 MHz, DMSO-d₆) δ 7.80 (s,1H), 7.27 (s, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H),6.99 (t, J = 6.7 Hz, 1H), 6.73 (s, 1H), 3.97-3.93 (m, 2H), 2.77 -2.72(m, 1H), 2.48 (s, 2H), 2.17-2.03 (m, 2H), 1.83-1.79 (m, 4H), 1.62-1.58(m, 1H), 1.38 (s, 9H), 1.33-1.31 (m, 2H) G-2-49

methyl 6-[5- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoyl-butoxy]-2- chlorophenyl] hex-5-ynoate [(M − 1)]⁻ = 465.20 (400 MHz,DMSO-d₆) 6 7.39 (d, J = 8.9 Hz, 1H), 7.25 (d, 1H), 7.06 (d, J = 3.0 Hz,1H), 6.94 (d, J = 8.9, 3.1 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.72 (d,1H), 3.86-3.88 (m, J = 5.9 Hz, 2H), 3.71-3.68 (m, 2H), 2.52 (d, J = 14.9Hz, 1H), 2.43-2.30 (m, 5H), 2.09-2.01 (m, 2H), 1.88-1.62 (m, 3H),1.60-1.56 (m, 1H), 1.39 (s, 9H) G-2-50 _

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-4-chlorophenyl] hex-5-ynoate 467.2 0 (400 MHz, DMSO-d₆) δ 7.38 (d, J =8.1 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 8.1,1.8 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.73 (m, 1H), 3.97-3.79 (m, 2H),3.76-3.53 (m, 1H), 3.32-3.08 (m, 1H), 2.48-2.26 ( m, 4H), 2.45- 2.26 (m,7H), 2.21-2.05 (m, 2H), 1.82-1.70 (m, 5H), 1.69-1.57 (m, 1H), 1.44-1.40(m, 1H), 1.36-1.24 (m, 1H) G-2-51

6-[3-[(3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpent-1-yn-1-yl]phenyl] hex-5-ynoic acid 413.10 (300 MHz, DMSO-d₆) δ 12.08 (s,1H), 7.73-7.13 (m, 6H), 6.76 (s, 1H), 4.45 (d, J = 7.9 Hz, 1H), 2.44 (d,J = 7.0 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 2.22 (td, J = 7.3, 2.5 Hz,2H),1.84 (q, J = 7.3 Hz, 2H), 1.75 (q, J = 7.2 Hz, 2H), 1.40 (s, 9H)G-2-52

benzyl(1r,4r)-4- [2-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol- 5-yl]ethynyl] cyclohexane-1- carboxylate 500.10 (400MHz, Chloroform-d) δ 8.15 (s, 1H), 7.44-7.31 (m, 5H), 7.15 (dd, J = 8.1,1.5 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 5.20(dd, J = 12.3, 5.1 Hz, 1H), 5.15 (s, 2H), 3.43 (s, 3H), 3.01-2.92 (m,1H), 2.91-2.66 (m, 2H), 2.50 (s, 1H), 2.54-2.35 (m, 1H), 2.31-2.22 m,1H), 2.18-1.98 (m, 4H), 1.60- 1.43 (m, 4H) G-2-53

(1s,4s)-4-((1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d] imidazol- 5-yl)ethynyl) cyclohexane-1- carboxylate 500.10(400 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.38 (d, J = 4.6 Hz, 5H), 7.16(dd, J = 8.1, 1.5 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 6.74 (d, J = 8.1Hz, 1H), 5.21 (dd, J = 12.6, 5.4 Hz, 1H), 5.16 (s, 2H), 3.44 (s, 3H),2.96 (dt, J = 19.6, 4.2 Hz, 2H), 2.79 (dtt, J = 38.0, 13.0, 6.7 Hz, 2H),2.45 (tt, J = 10.3, 3.6 Hz, 1H), 2.26 (dq, J = 13.0, 3.1, 2.3 Hz, 1H),2.14-1.93 (m, 3H), 1.90 (dtd, J = 17.5, 8.9, 4.2 Hz, 3H), 1.73-1.61 (m,2H) G-2-54

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-5-chlorophenyl] hex-5-ynoate 467.05 (400 MHz, DMSO-d₆) δ 7.26 (s, 1H),7.04-6.99 (m, 2H), 6.92 (t, J = 1.8 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H),6.73 (s, 1H), 4.48-4.34 (m, 1H), 3.91 (d, J = 5.8 Hz, 2H), 3.60 (s, 3H),2.15-2.09 (m, 2H), 1.79 (d, J = 7.3 Hz, 2H), 1.76-1.69 (m, 2H), 1.62 (d,J = 14.1 Hz, 2H), 1.58-1.46 (m, 2H), 1.38 (s, 9H) G-2-55

6-[3-(2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-methylphenyl] hex-5-ynoic acid [(M − 1)]⁻ = 431.05 (400 MHz, DMSO-d₆)δ 12.12 (s, 1H), 7.69-7.52 (m, 2H), 7.27 (s, 1H), 7.10 (t, J = 7.9 Hz,1H), 6.93 (dd, J = 12.1, 7.9 Hz, 2H), 6.83 (d, J = 8.3 Hz, 1H), 6.73 (s,1H), 3.92- 3.88 (m, 1H), 3.86-3.70 (m, 2H), 2.40 (t, J = 6.9 Hz, 2H),2.23 (s, 3H), 2.15-2.09 (m, 2H), 1.86-1.73 (m, 3H), 1.68-1.52 (m, 1H),1.39 (s, 9H) G-2-56

6-[3-[(2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]hex- 5-ynoate 433.30 (400 MHz, DMSO-d₆) δ 7.56 (td, J = 7.4, 2.5Hz, 1H), 7.28-7.21 (m, 1H), 6.96 (dt, J = 7.6, 1.2 Hz, 1H), 6.91 (dd, J= 7.0, 1.1 Hz, 2H), 6.82 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 3.90-3.86(m, 2H), 3.72-3.68 (m, 1H), 3.61 (s, 3H), 2.47 (s, 3H), 2.20-2.03 (m,2H), 1.82-1.78 (m, 4H), 1.61 (s, 1H), 1.39 (s, 9H) G-2-57

6-[4-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-3-fluorophenyl] hex-5- ynoic acid [(M − 1)]⁻ = 435.05 (400 MHz, DMSO-d₆)δ 12.08 (s, 1H), 7.62 (d, J =10.4 Hz, 1H), 7.60-7.51 (m, 1H), 7.27 (s,1H), 7.22-7.13 (m, 1H), 6.83 (d, J = 8.5 Hz, 1H),6.74 (s, 1H), 3.98-3.94(m, 2H), 3.74-3.70 (m, 1H), 2.48-2.33 (m, 2H), 2.21-2.04 (m, 2H), 1.79(s, 1H), 1.78-1.76 (m, 2H), 1.38-1.35 (m, 9H), 1.34-1.31 (m, 1H), 1.30-1.20 (m, 1H), 0.90-0.82 (m, 1H) G-2-58

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoyl-butanamido] phenyl]hex- 5-ynoate 446.15 (300 MHz, DMSO-d₆) δ 10.02 (s,1H), 7.71 (t, J = 1.8 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.27 (t, J =7.9 Hz, 2H), 7.08-7.04 (m, 2H), 6.76 (s, 1H), 4.00 (q, J = 7.5 Hz, 1H),3.60 (s, 3H), 2.47-2.44 (m, 4H), 2.14 (q, J = 7.7 Hz, 2H), 1.87-1.75 (m,4H), 1.38 (s, 9H) G-2-59

6-(3-[[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2-yl]oxy] phenyl)hex- 5-ynoic acid 433.15 (400 MHz, DMSO-d₆) δ 7.79 (s,1H), 7.26-7.21 (m, 2H), 6.94 (d, J = 7.5 Hz, 1H), 6.88-6.86 (m, 2H),6.81-6.66 (m, 2H), 4.36-4.31 (m, 1H), 3.56-3.44 (m, 1H), 3.17 (s, 1H),2.46-2.39 (m, 3H), 2.14-2.00 (m, 2H), 1.87-1.76 (m, 3H), 1.58- 1.45 (m,1H), 1.38 (s, 9H), 1.17 (d, J = 5.9 Hz, 3H) G-2-60

methyl 5-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]pent- 4-ynoate 419.05 (400 MHz, DMSO-d₆) δ 7.26 (s, 1H), 7.25 (t,J = 7.9 Hz, 1H), 6.99- 6.86 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.72 (s,1H), 3.90-3.86 (m, 2H), 3.73-3.69 (m, 1H), 3.64 (s, 3H), 2.71-2.56 (m,4H), 2.21-2.03 (m, 2H), 1.86-1.73 (m, 1H), 1.67- 1.53 (m, 1H), 1.39 (s,9H) G-2-61

6-[5-[(2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-methylphenyl] hex-5-ynoic acid 433.05 (400 MHz, DMSO-d₆) δ 12.06 (s,1H), 7.25 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 2.7 Hz, 1H),6.85-6.77 (m, 2H), 6.75 (s, 1H), 3.89-3.78 (m, 2H), 3.70-3.68 (m, 2H),2.41-2.39 (m, 2H), 2.27-2.25 (m, 3H), 2.11-2.09 (m, 2H), 1.78 (s, 3H),1.60-1.58 (m, 2H), 1.39 (s, 9H) G-2-62

6-[3-[(2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-5-methylphenyl] hex-5-ynoic acid [(M − 1)]⁻ = 431.05 (400 MHz, DMSO-d₆)δ 12.09 (s, 1H), 7.25 (s, 1H), 6.80 (d, J = 4.7 Hz, 2H), 6.75-6.71 (m,3H), 3.91-3.80 (m, 2H), 3.71-3.67 (m, 1H), 2.41 (d, J = 24.6, 7.2 Hz,3H), 2.24-2.20 (m, 3H), 2.18-2.06 (m, 3H), 1.78-1.74 (m, 2H), 1.62-1.58(m, 1H), 1.39 (s, 9H), 1.28 -1.24 (m, 1H) G-2-63

6-[3-[(2S)- 2-[(tert- butoxycarbonyl) amino]4- carbamoylbutoxy]-4-methylphenyl] hex-5-ynoic acid 433.20 (400 MHz, DMSO-d₆) δ 12.13 (s,1H), 7.27 (s, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 9.3, 1.8 Hz,2H), 6.80 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 3.94-3.90 (m, 1H), 3.86-3.71 (m, 2H), 2.44-2.40 (m, 2H), 2.40-2.36 (m, 2H), 2.15-2.11 (m, 5H),1.75-.72 (m, 2H), 1.68-1.54 (m, 2H), 1.39 (s, 9H) G-2-64

6-[5-[(2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluorophenyl] hex-5-ynoic acid 437.05 (400 MHz, DMSO-d₆) δ 12.09 (s,1H), 7.25 (s, 1H), 7.16 (t, J = 9.1 Hz, 1H), 6.98 (dd, J = 5.8, 3.1 Hz,1H), 6.95-6.91 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H),3.91-3.80 (m, 2H), 3.69 (s, 1H), 2.50-2.48 (m, 2H), 2.39 (t, J = 7.4 Hz,2H), 2.13- 2.09 (m, 2H), 1.79-1.75 (m, 3H), 1.62-1.58 (m, 1H), 1.39 (s,9H) G-2-65

6-[3-[(2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-5-fluorophenyl] hex-5-ynoic acid 437.05 (400 MHz, DMSO-d₆) δ 12.09 (s,1H), 7.56-7.53 (m, 2H), 7.26 (s, 1H), 6.876.77 (m, 3H), 3.91 (d, J = 5.9Hz, 2H), 3.73-3.69 (m, 1H), 2.46 (t, J = 7.0 Hz, 2H), 2.38 (t, J = 7.7Hz, 2H), 2.20-2.05 (m, 2H), 1.85-1.69 (m, 3H), 1.61-1.57 (m, 1H), 1.39(s, 9H) G-2-66

methy 5-[4- ([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy]methyl)- 2-methylphenyl] pent-4-ynoate461.25 (400 MHz, Methanol-d₄) δ 7.28 (d, J = 7.9 Hz, 1H), 7.21 (s, 1H),7.12 (d, J = 7.9 Hz, 1H), 4.60-4.42 (m, 2H), 3.72 (s, 3H), 3.70-3.68 (m,3H), 3.62-3.55 (m, 1H), 3.53-3.47 (m, 1H), 2.76 (t, J = 7.0 Hz, 2H),2.65 (t, J = 7.1 Hz, 2H), 2.38 (s, 3H), 2.33-2.19 (m, 2H), 2.02-1.94 (m,1H), 1.68-1.58 (m, 1H), 1.45 (s, 9H), 1.18 (d, J = 6.2 Hz, 3H) G-2-67

6-(3-[[2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoyl- butanamido]methyl]phenyl) hex-5-ynoic acid 446.20 (400 MHz, DMSO-d₆) δ 12.11 (s,1H), 8.40-8.27 (m, 1H), 7.29-7.25 (m, 3H), 7.22-7.20 (m, 1H), 6.95 (d, J= 7.8 Hz, 1H), 6.76 (s, br, 1H), 4.35-4.17 (m, 2H), 3.89 (q, J = 7.7 Hz,1H), 2.45 (t, J = 7.0 Hz, 2H), 2.41-2.29 (m, 3H), 2.26-2.19 (m, 1H),2.13-2.11 (m, 1H), 1.87-1.83 (m, 1H), 1.74-1.70 (m, 3H), 1.39 (s, 9H)G-2-68

tert-butyl N- [(3S,4R)-1- carbamoyl-4- ([4-[3-(1-[[(2S)- 1-[(2S,4R)-4-hydroxy-2-([[4- (4-methyl-1,3- thiazol-5- yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl] carbamoyl]cyclopropyl)prop- 1-yn-1-yl]phenyl] methoxy)pentan- 3-yl]carbamate871.40 (400 MHz, Methanol-d₄) δ 8.90 (s, 1H), 7.66 (dd, J = 12.7, 7.4Hz, 1H), 7.58 (td, J = 8.2, 7.8, 3.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H),7.46-7.39 (m, 1H), 7.35 (d, J = 11.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H),4.75 (d, J = 13.4 Hz, 1H), 4.65-4.42 (m, 5H), 4.35 (d, J = 15.5 Hz, 1H),3.93- 3.78 (m, 2H), 3.60 (dd, J = 10.1, 6.2 Hz, 1H), 3.58-3.44 (m, 1H),3.03 (d, J = 18.1Hz, 1H), 2.67 (d, J = 9.1 Hz, 1H), 2.47 (d, J = 12.3Hz, 3H), 2.27 (dt, J = 19.9, 9.8 Hz, 3H), 2.11- 1.98 (m, 1H), 1.97 (d, J= 11.7 Hz, 1H), 1.62 (d, J = 15.1 Hz, 1H), 1.45 (d, J = 5.0 Hz, 9H),1.33-1.23 (m, 1H), 1.17 (dd, J = 10.4, 6.3 Hz, 4H), 1.06 (d, J = 9.9 Hz,9H), 1.02 (d, J = 8.0 Hz, 1H), 0.88 (q, J = 3.8, 3.3 Hz, 1H) G-2-69

6-[3-[(1E,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpent-1-en-1-yl]phenyl] hex-5-ynoic acid 415.10 (400 MHz, DMSO-d₆) δ 12.13 (s,(s, 1H), 6.40 (d, J = 15.9 Hz, 1H), 6.21 (dd, J = 16.0, 6.6 Hz, 1H),4.08-4.02 (m, 1H), 2.47 (t, J = 6.9 Hz, 2H), 2.44-2.36 (m, 2H), 2.13-2.10 (m, 2H), 1.82-1.69 (m, 4H), 1.40 (s, 9H) G-2-70

methyl 5-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)- amino]5-carbamoylpentan- 2-yl]oxy]methyl)- 3-fluorophenyl] pent-4-ynoate 465.20(400 MHz, DMSO-d₆) δ 7.43 (t, J = 7.7 Hz, 1H), 7.21-7.17 (m, 3H), 6.68(s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.52 (q, J = 12.4 Hz, 2H), 3.64 (s,3H), 3.46-3.40 (m, 2H), 2.70- 2.61 (m, 4H), 2.11-1.97 (m, 2H), 1.80-1.72(m, 1H), 1.37 (s, 9H), 1.34 (s, 1H), 1.07 (d, J = 5.6 Hz, 3H) G-2-71

methyl 5-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2-yl]oxy]methyl)- 3-methylphenyl] pent-4-ynoate 461.24(400 MHz, DMSO-d₆) δ 7.67-7.52 (m, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.22(s, 1H), 7.18-7.12 (m, 2H), 6.68 (s, 1H), 6.60 (d, J = 8.7 Hz, 1H), 4.45(q, J = 12.1 Hz, 2H), 3.61 (d, J = 10.2 Hz, 1H), 3.43 (h, J = 6.8, 5.8Hz, 2H), 3.32 (d, J = 9.6 Hz, 1H), 2.64 (dq, J = 12.2, 6.2 Hz, 4H), 2.55(d, J = 5.3 Hz, 1H), 2.23 (s, 3H), 2.12-1.97 (m, 2H), 1.81-1.73 (m, 1H),1.38 (s, 9H), 1.08 (d, J = 5.6 Hz, 3H) G-2-72

methyl 5-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluoro-5- methylphenyl] pent-4-ynoate 451.20 (400 MHz, DMSO-d₆) δ 7.26(s, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.80-6.71(m, 2H), 3.95-3.90 (m, 2H), 3.76-3.68 (m, 1H), 3.64 (s, 3H), 2.70 (dd, J= 7.6, 5.6 Hz, 2H), 2.64-2.58 (m, 2H), 2.23 (s, 3H), 2.16-2.07 (m, 2H),1.85-1.73 (m, 1H), 1.66-1.52 (m, 1H), 1.39 (s, 9H) G-2-73

methyl 5-[4- [(2E,4S)-4-[(tert- butoxycarbonyl) amino]-6- carbamoylhex-2-en-1-yl] phenyl]pent- 4-ynoate 429.25 (400 MHz, DMSO-d₆) δ 7.29 (d, J=7.9 Hz, 2H), 7.23 (s, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.8Hz, 1H), 6.71 (s, 1H), 5.67-5.51 (m, 1H), 5.46-5.31 (m, 1H), 3.87-3.85(m, 1H), 3.65 (s, 3H), 3.35-3.31 (m, 2H), 2.74-2.56 (m, 4H), 2.04 (t, J= 7.7 Hz, 2H), 1.68-1.57 (m, 2H), 1.38 (s, 9H) G-2-74

methyl 6-[6- [(1S)-3- carbamoyl-1-[(2- methylpropane- 2-sulfinyl)amino]propyl] pyridin-3-yl]hex-5- ynoate 408.15 (400 MHz, DMSO-d₆) δ8.45 (s, 1H), 7.72-7.71 (m, 1H), 7.45-7.43 (d, J = 8.0 Hz, 1H), 7.28 (s,1H), 6.78 (s, 1H), 5.75-5.74 (d, J = 5.3 Hz, 1H), 4.33-4.28 (m, 1H),3.61 (s, 3H), 2.48 (s, 2H), 2.47 (s, 1H), 2.19-1.99 (m, 4H), 1.86-1.78(m, 3H), 1.08 (s, 9H) G-2-75

methyl 5-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-chlorophenyl] pent-4-ynoate 453.10 (300 MHz, DMSO-d₆) δ 7.31-7.20 (m,2H), 7.15 (d, J = 8.2 Hz, 1H), 7.11-7.03 (m, 1H), 6.83 (d, J = 8.4 Hz,1H), 6.75 (s, 1H), 3.96 (dd, J = 6.2, 3.0 Hz, 2H), 3.78 (s, 1H), 3.65(s, 3H), 2.80-2.59 (m, 4H), 2.16- 2.12 (m, 2H), 1.85-1.81 (s, 1H),1.63-1.59 (m, 1H), 1.40 (s, 9H) G-2-76

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-5-chloro-2- fluorophenyl]hex- 5-ynoate 485.20 (300 MHz, DMSO-d₆) δ7.37-7.33 (m, 1H), 7.27 (s, 1H), 7.10-7.08 (m, 1H) , 6.85 (d, J = 8.4Hz, 1H), 6.74 (s, 1H), 4.03-3.98 (m, 3H), 3.74- 3.72 (m, 1H), 3.61 (s,3H), 2.15- 2.12 (m, 2H), 1.87-1.69 (m, 6H), 1.62-1.58 (m, 1H), 1.39 (s,9H) G-2-77

methyl 5-(3- [2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutanamido]-2-chlorophenyl) pent-4-ynoate 466.20 (400 MHz, DMSO-d₆) δ 9.45 (s, 1H),7.87-7.79 (m, 1H), 7.63 (td, J = 6.2, 5.1, 3.4 Hz, 1H), 7.63-7.52 (m,1H), 7.29 (d, J = 4.8 Hz, 2H), 6.81 (s, 1H), 4.13 (s, 1H), 3.64 (s, 3H),2.75 (dd, J = 7.4, 5.8 Hz, 2H), 2.65 (dd, J = 7.4, 5.8 Hz, 2H), 2.20 (d,J = 8.1 Hz, 2H), 2.00 (s, 1H), 1.83-1.79 (m, 1H), 1.41 (s, 9H) G-2-78

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4-carbamoylbutanamido]- 2-chlorophenyl] hex-5-ynoate 480.20 (300 MHz,DMSO-d₆) δ 9.76 (s, 1H), 7.87-7.81 (m, 1H), 7.72-7.50 (m, 4H), 7.32 (s,1H), 7.23 (t, J = 6.9 Hz, 1H), 7.15 (t, J = 7.8 Hz, 2H), 6.81 (s, 1H),4.20-4.14 (m, 1H), 3.62 (s, 3H), 2.23-2.16 (m, 2H), 2.01-1.72 (m, 4H),1.41 (s, 9H) G-2-79

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4-carbamoylbutanamido]- 2-fluorophenyl] hex-5-ynoate 464.15 (300 MHz,DMSO-d₆) δ 9.45 (s, 1H), 7.84 (d, J = 4.9 Hz, 1H), 7.41- 7.19 (m, 4H),6.82 (s, 1H), 4.17- 4.12 (m, 1H), 3.34 (s, 3H), 2.59- 2.54 (m, 4H),2.23-2.19 (m, 2H), 2.04-1.97 (m, 1H), 1.90-1.80 (m, 3H), 1.42 (s, 9H)G-2-80

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluoro-6- methylphenyl] hex-5-ynoate 465.15 (400 MHz, DMSO-d₆) δ 7.26(s, 1H), 7.17-6.95 (m, 2H), 6.84 (dd, J = 8.5, 5.4 Hz, 1H), 6.74 (s,1H), 4.00-3.88 (m, 2H), 3.72 (s, 1H), 3.61 (s, 3H), 2.60-2.52 (m, 2H),2.30 (s, 3H), 2.20-2.03 (m, 2H), 1.88-1.73 (m, 2H), 1.66-1.57 (m, 2H),1.58-1.43 (m, 2H), 1.38 (s, 9H) G-2-81

6-[3-[(2S)- 2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxyl-2,6-difluorophenyl] hex-5-ynoate 469.15 (400 MHz, DMSO-d₆) δ 7.22 (dd, J= 15.2, 9.7 Hz, 2H), 7.10-7.06 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.73(s, 1H), 3.97-3.93 (m, 2H), 3.74- 3.69 (m, 1H), 3.61 (s, 3H), 2.59- 2.55(m, 2H), 2.51-2.38 (m, 2H), 2.19-2.03 (m, 1H), 1.88-1.72 (m, 4H),1.61-1.56 (m, 1H), 1.38 (s, 9H) G-2-82

tert-butyl N-(4- carbamoyl-1-[[2- fluoro-3-(4- hydroxybut-1-yn-1-yl)phenyl] (methyl)amino] butan-2- yl)carbamate 408.15 (400 MHz,DMSO-d₆) δ 7.22 (s, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.94- 6.82 (m, 2H),6.69 (s, 1H), 6.57 (d, J = 9.1 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H),3.61-3.57 (m, 2H), 3.32 (d, J = 9.5 Hz, 2H), 3.17-3.07 (m, 2H), 2.81 (s,3H), 2.59 (t, J = 6.9 Hz, 2H), 2.07-2.03 (m, 2H), 2.09-1.99 (m, 1H),1.34 (s, 9H) G-2-83

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4-carbamoylbutanamido]- 5-chlorophenyl] hex-5-ynoate 480.20 (400 MHz,CDCl₃) δ 9.75 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 7.12 (t, J = 1.6 Hz,1H), 6.22 (d, J = 38.6 Hz, 2H), 5.82 (s, 1H), 4.43 (s, 1H), 3.72 (s,3H), 2.59-2.43 (m, 6H), 2.33- 2.22 (m, 1H), 2.12-1.94 (m, 3H), 1.48 (s,9H) G-2-84

Methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4-carbamoylbutanamido]- 5-methylphenyl] hex-5-ynoate 460.20 (300 MHz,DMSO-d₆) δ 9.94 (s, 1H), 7.52 (s, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.06(d, J = 7.5 Hz, 1H), 6.92 (s, 1H), 6.79 (s, 1H), 4.02 (q, J = 7.4 Hz,1H), 3.62 (s, 3H), 2.53- 2.44 (m, 3H), 2.26 (s, 3H), 2.23- 2.03 (m, 3H),1.87-1.78 (m, 4H), 1.40 (s, 9H) G-2-85

methyl 6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4-carbamoylbutanamido]- 2-methylphenyl] hex-5-ynoate 460.25 (400 MHz,DMSO-d₆) δ 9.40 (s, 1H), 7.35-7.29 (m, 2H), 7.22 (dd, J =7.7, 1.5 Hz,1H), 7.15 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H),4.10-4.01 (m, 1H), 3.61 (s, 3H), 2.26 (s, 3H), 2.25-2.11 (m, 4H),1.98-1.92 (m, 2H), 1.86- 1.81 (m, 4H), 1.41 (s, 9H) G-2-86

methyl 5-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluorophenyl] pent-4-ynoate 437.15 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H),7.18 (t, J = 8.2, 1.6 Hz, 1H), 7.07 (t, J = 8.1, 1.2 Hz, 1H), 6.97 (m,1H), 6.85 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 3.97-3.93 (m, 2H),3.75-3.71 (m, 1H), 3.64 (s, 3H), 2.72 (t, J = 5.7 Hz, 2H), 2.64-2.62 (m,2H), 2.17-2.05 (m, 2H), 1.84- 1.74 (m, 1H), 1.61-1.57 (m, 1H), 1.38 (s,9H) G-2-87

methyl 6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4-carbamoylbutanamido]- 5-fluorophenyl] hex-5-ynoate 464.25 (300 MHz,DMSO-d₆) δ 10.23 (s, 1H), 7.59-7.50 (m, 1H), 7.48 (s, 1H), 7.30 (s, 1H),7.13 (d, J = 7.3 Hz, 1H), 6.99-6.87 (m, 1H), 6.80 (s, 1H), 4.12-3.93 (m,1H), 3.62 (s, 3H), 2.50-2.44 (m, 4H), 2.26-2.08 (m, 2H), 1.98-1.74 (m,4H), 1.40 (s, 9H) G-2-88

methyl 6-[3- ([2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutyl]amino)-2- fluorophenyl] hex-5-ynoate 450.30 (400 MHz, DMSO-d₆) δ 7.25(s, 1H), 6.90-6.76 (m, 1H), 6.72 (s, 1H), 6.60 (t, J = 8.2 Hz, 1H), 6.41(t, J = 7.1 Hz, 2H), 5.23 (s, 1H), 3.60-3.56 (m, 4H), 3.18 (s, 1H),3.09-3.05 (m, 1H), 2.52 (d, J = 15.5 Hz, 1H), 2.31-2.27 (m, 2H), 2.16-1.98 (m, 1H), 1.91-1.87 (m, 1H), 1.79-1.75 (m, 1H), 1.62-1.47 (m, 4H),1.29 (s, 9H) G-2-89

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluoro-5- methylphenyl] hex-5-ynoate 465.25 (400 MHz, DMSO-d₆) δ 7.26(s, 1H), 7.03-6.96 (m, 1H), 6.87-6.77 (m, 2H), 6.74 (s, 1H), 3.99-3.87(m, 2H), 3.78-3.66 (m, 1H), 3.61 (s, 3H), 2.49-2.44 (m, 2H), 2.24 (s,3H), 2.18-2.05 (m, 4H), 1.85-1.74 (m, 3H), 1.65-1.52 (m, 1H), 1.39 (s,9H) G-2-90

methyl 6-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2,5-difluorophenyl] hex-5-ynoate 469.05 (400 MHz, CDCl₃) δ 6.74-6.62 (m,2H), 6.20 (s, 1H), 5.45 (s, 1H), 5.06 (s, 1H), 4.04 (br, 3H), 3.72 (s,3H), 2.55 (td, J = 7.1, 4.7 Hz, 4H), 2.38 (t, J = 6.9 Hz, 2H), 2.13-1.98(m, 4H), 1.48 (s, 9H) G-2-91

methyl 6-[2- [(1S)-3-carbamoyl- 1-[(2-methylpropane- 2-sulfinyl)amino]propyl]pyridin- 4-yl]hex- 5-ynoate 408.15 (400 MHz, DMSO-d₆) δ 8.58-8.37(m, 1H), 7.43 (s, 1H), 7.31-7.29 (d, J = 4.7 Hz, 2H), 6.80 (s, 1H),5.81- 5.79 (d, J = 5.8 Hz, 1H), 4.29-4.25 (m, 1H), 3.61 (s, 3H),2.49-2.47 (d, J = 9.3 Hz, 3H), 2.18-2.01 (m, 3H), 1.89-1.78 (m, 3H),1.09 (s, 9H) G-2-92

methyl 5-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4-carbamoylbutanamido] phenyl]pent- 4-ynoate 432.20 (300 MHz, DMSO-d₆) δ10.02 (s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.53- 7.50 (m, 1H), 7.35-7.20(m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.78 (s, 1H), 4.06-4.01 (m, 1H), 3.66(s, 3H), 2.71-2.60 (m, 5H), 2.20-2.12 (m, 2H), 1.99-1.70 (m, 2H), 1.40(s, 9H) G-2-93

tert-butyl N- [(2S)-4- carbamoyl-1- [2-fluoro-3-(4- hydroxybut-1-yn-l-yl)phenoxy] butan-2- yl]carbamate 395.25 (400 MHz, DMSO-d₆) δ 7.27(s, 1H), 7.17 (td, J = 8.1, 1.7 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H),7.01-6.99 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 4.92 (s, 1H),3.95 (d, J = 6.1 Hz, 2H), 3.75-3.70 (m, 1H), 3.59 (t, J = 6.8 Hz, 2H),2.60 (t, J = 6.8 Hz, 2H), 2.21-2.03 (m, 2H), 1.79 (s, 1H), 1.59 (s, 1H),1.39 (s, 9H) G-2-96

methyl 5-[3- [(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluoro-5- methylphenyl] pent-4-ynoate 451.20 (400 MHz, DMSO-d₆) δ 7.26(s, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.80-6.71(m, 2H), 3.95-3.90 (m, 2H), 3.76-3.68 (m, 1H), 3.64 (s, 3H), 2.70 (dd, J= 7.6, 5.6 Hz, 2H), 2.64-2.58 (m, 2H), 2.23 (s, 3H), 2.16-2.07 (m, 2H),1.85-1.73 (m, 1H), 1.66-1.52 (m, 1H), 1.39 (s, 9H)

Tert-butyl(2E)-3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-enoate(Intermediate G-2-13)

To a mixture of3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(1.00 g, 3.00 mmol), tert-butyl-prop-2-enoate (3.79 g, 29.6 mmol), DIEA(0.76 g, 5.90 mmol) and Pd₂(dba)₃ (0.27 g, 0.30 mmol) in DMA (30.0 mL)was added P(t-Bu)₃ (10% in hexane, 1.20 g, 0.59 mmol) at roomtemperature under nitrogen atmosphere. The mixture was purged withnitrogen for 3 times and stirred for 16 hours at 80° C. under nitrogenatmosphere. The mixture was cooled down to room temperature andconcentrated under reduced pressure. The residue was purified byreversed phase flash chromatography with the following conditions:Column: WelFlash™ C18-I, 20-40 m, 330 g; Eluent A: water (plus 10 mmol/LHOAc); Eluent B: ACN; Gradient: 30%-50% B in 25 min; Flow rate: 80mL/min; Detector: UV 220/254 nm; desired fractions were collected at 39%B and concentrated under reduced pressure to afford the title compoundas a brown solid (0.91 g, 80%): ¹H NMR (400 MHz, CDCl₃). 7.62 (d, J=15.9Hz, 1H), 7.27-7.18 (m, 2H), 6.82 (d, J=8.1 Hz, 1H), 6.35 (d, J=15.9 Hz,1H), 5.24 (dd, J=12.7, 5.3 Hz, 1H), 3.48 (d, J=1.2 Hz, 3H), 2.98 (d,J=17.0 Hz, 1H), 2.92-2.74 (m, 2H), 2.27 (dd, J=10.2, 5.3 Hz, 1H), 1.56(s, 9H); MS (ESI, m/z): [(M+1)]⁺=386.25.

The following intermediate in Table 26 below was prepared according tothe above procedure to prepare Intermediate G-2-13.

TABLE 26 Characterization data for intermediate prepared according toprocedure above. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺¹H-NMR G-2-14

(2E)-3-4- ([[(2R,3S)-3- [(tert-butoxycarbonyl) amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl] prop-2-enoate 463.4  (400 MHz,CDCl₃) δ 7.60 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 6.38 (d, J = 15.9 Hz, 2H), 5.42 (s, 1H), 4.87 (d, J = 9.6Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 3.77-3.61(m, 2H), 2.34-2.27 (m, 2H), 2.00 (d, J = 7.8 Hz, 1H), 1.78-1.66 (m, 1H),1.51 (s, 9H), 1.45 (s, 9H), 1.23 (d, J = 6.4 Hz, 3H). G-2-15

tert-butyl (2E)-3-[6- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan-2- yl]oxy]methyl)naphthalen- 2-yl]prop-2-enoate 513.3 (400 MHz, CD₃OD) δ 8.01 (s, 1H), 7.93-7.72 (m, 2H), 7.56 (d, J = 8.3 Hz,1H), 7.46 (dd, J = 5.0, 1.9 Hz, 2H), 7.29 (dd, J = 16.0, 1.3 Hz, 1H),6.56 (d, J = 15.9 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.69 (d, J = 12.1Hz, 1H), 3.68-3.53 (m, 2H), 2.35-2.19 (m, 2H), 2.11-1.96 (m, 1H), 1.72-1.63 (m, 1H), 1.57 (s, 9H), 1.42 (s, 9H), 1.23 (d, J = 6.1 Hz, 3H).G-2-43

ethyl (2E)-3-[7- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2- yl]oxy]methyl)naphthalen- 2-yl]prop-2-enoate 485.25(400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.95-7.86 (m, 4H), 7.80 (d, J = 16.0Hz, 1H), 7.54 (dd, J = 8.4, 1.6 Hz, 1H), 7.25 (s, 1H), 6.80-6.65 (m,3H), 4.70-4.61 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.04-4.02 (m, 1H),3.52-3.47 (m, 2H), 2.12-2.08 (m, 2H), 1.88-1.80 (m, 1H), 1.59-1.45 (m,1H), 1.37 (s, 9H), 1.30-1.26 (m, 2H), 1.11 (d, J = 5.9 Hz, 3H) G-2-44

ethyl (2E)-3-[6- ([[2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoyl-pentan-2-yl]oxy]methyl) naphthalen-1-yl]prop-2- enoate 485.15 (400 MHz,DMSO-d₆) δ 8.43 (d, J = 15.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H),8.02-7.91 (m, 3H), 7.63-7.52 (m, 2H), 7.24 (s, 1H), 6.69 (dd, J = 8.4Hz, 3H), 4.74-4.62 (m, 2H), 4.26-4.23 (m, 2H), 3.49-3.45 (m, 2H),2.08-2.04 (m, 2H), 1.90- 1.78 (m, 1H), 1.53-1.49 (m, 1H), 1.36 (s, 9H),1.30 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 5.5 Hz, 3H) G-2-45

methyl 3-[[4- ([[2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-cabamoyl-pentan-2-yl]oxy]methyl) phenyl]methylidene] cyclobutane-1- carboxylate461.25 (400 MHz, CDCl₃) δ 7.51-7.47 (m, 1H), 7.38-7.32 (m, 1H),7.24-7.15 (m, 2H), 5.41 (s, 1H), 4.86 (dd, J = 18.0, 9.3 Hz, 1H), 4.56(d, J = 11.8 Hz, 1H), 4.42-4.37 (m, 1H), 3.75 (s, 3H), 3.72-3.59 (m,2H), 3.42-2.93 (m, 2H), 2.29 (td, J = 8.3, 7.6, 3.3 Hz, 2H), 2.05-1.60(m, 4H), 1.45 (s, 9H), 1.23-1.18 (m, 3H) G-2-46

tert-butyl 2-(4-((1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5- yl)methylene)cyclohexyl)acetate 468.25 (300 MHz, CDCl₃) δ 8.26 (s, 1H), 6.96-6.88 (m,1H), 6.86 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 5.26-5.23 (m,1H), 3.44 (s, 3H), 3.02-2.66 (m, 4H), 2.45-2.19 (m, 3H), 2.17 J = 6.9Hz, 2H), 2.05- 1.78 (m, 2H), 1.62-1.60 (m, 1H), 1.48 (s, 11H), 1.25-1.02(m, 1H) G-2-94

3-(5-[1,4-dioxaspiro[4.5] decan-8-ylidenemethyl]-3- methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine- 2,6-dione 412.20 (400 MHz, DMSO-d₆) δ 11.10(s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 1.4 Hz, 1H), 6.91-6.88(m, 1H), 6.37-6.35 (m, 1H), 5.38-5.35 (m, 1H), 3.93-3.84 (m, 4H), 3.37-3.35 (m, 1H), 3.31 (d, J = 16.7 Hz, 1H), 2.96-2.94 (m, 1H), 2.93-2.86(m, 1H), 2.80-2.78 (m, 1H), 2.74- 2.59 (m, 2H), 2.48-2.46 (m, 1H),2.38-2.36 (m, 1H), 2.05-1.99 (m, 1H), 1.98-1.96 (m, 1H), 1.72-1.69 (m,2H), 1.63-1.60 (m, 2H)

Methyl (5E)-6-[4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]hex-5-enoate(Intermediate G-2-47)

To a stirred solution of tert-butylN-[(3S,4R)-1-carbamoyl-4-[(4-ethenylphenyl)methoxy]pentan-3-yl]carbamate(480 mg, 1.33 mmol) and methyl hex-5-enoate (509 mg, 3.97 mmol) in DCM(5.00 mL) was added Grubbs 2nd (112 mg, 0.13 mmol) in portions at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredfor 16 h at room temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The crude product waspurified by reverse phase flash chromatography with the followingconditions: Column: Spherical C¹⁸ Column, 20-40 um, 120 g; Mobile PhaseA: water (plus 0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min;Gradient: 20% B to 40% B in 25 min, Detector: UV 220/254 nm. Thefractions containing the desired product were collected at 35% B andconcentrated under reduced pressure to afford the title compound as awhite solid (390 mg, 64%): ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J=7.9 Hz,2H), 7.30-7.24 (m, 2H), 6.41 (d, J=15.9 Hz, 1H), 6.23-6.19 (m, 1H),5.41-5.38 (m, 2H), 4.87 (d, J=9.6 Hz, 1H), 4.60 (d, J=12.0 Hz, 1H), 4.39(d, J=11.8 Hz, 1H), 3.69-3.60 (m, 1H), 2.39 (t, J=7.5 Hz, 2H), 2.34-2.25(m, 4H), 2.11-1.94 (m, 2H), 1.88-1.80 (m, 2H), 1.75-1.67 (m, 4H), 1.45(s, 9H), 1.21 (d, J=6.5 Hz, 3H); LC/MS (ESI, m/z): [(M+Na)]⁺=485.20

The intermediates in Table 27 were prepared according to the aboveprocedure to prepare Intermediate G-2-47.

TABLE 27 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-2-48

ethyl (4E)-5-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino-5-carbamoyl-pentan-2-yl]oxy] methyl)phenyl]pent- 4-enoate [(M + Na)]⁺ = 485.20 Usedin the next step without further purification G-2-95

methyl (4S,5E)-7- (4-bromophenyl)- 4-[(tert-butoxy- carbonyl)amino]hept-5-enoate 412.10, 414.10 (400 MHz, DMSO-d₆) δ 7.47 (d, J = 8.0 Hz,2H), 7.15 (d, J = 8.0 Hz, 2H), 6.80 (s, 1H), 5.61 (dt, J = 14.2, 6.7 Hz,1H), 5.40 (dd, J = 15.3, 6.7 Hz, 1H), 3.90 (s, 1H), 3.57 (s, 3H), 3.30(d, J = 6.7 Hz, 2H), 2.27 (t, J = 7.7 Hz, 2H), 1.65 (dq, J = 13.1, 6.5Hz, 2H), 1.37 (s, 9H)

Step 3. tert-butyl2-[2-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]ethoxy)ethoxy]acetate.The titled compound was prepare according to the procedure of Step 4 ofthe procedure to prepare Intermediate B. ¹H NMR (400 MHz, DMSO-d₄) δ11.09 (s, 1H), 7.08-6.97 (m, 2H), 6.90-6.85 (m, 1H), 5.34 (dd, J=12.7,5.4 Hz, 1H), 3.99 (d, J=1.0 Hz, 3H), 3.51-3.44 (m, 4H), 3.39 (t, J=6.5Hz, 2H), 3.33 (s, 4H), 3.01-2.84 (m, 1H), 2.78-2.57 (m, 4H), 2.08-1.95(m, 1H), 1.80 (dq, J=14.2, 6.8 Hz, 2H), 1.41 (s, 9H), 1.35 (s, 2H); MS(ESI, m/z): [(M+23)]⁺=542.3.

The following intermediates in Table 28 were prepared according to theprocedure of Step 3 of the procedure to prepare Intermediate G.

TABLE 28 Intermediates prepare according to Step 3 above. Inter- MS:mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMR G-3-2

tert-butyl 3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propanoate 388.3 (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 7.08 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.92-6.86(m, 1H), 5.34 (dd, J = 12.8, 5.4 Hz, 1H), 3.34 (s, 1H), 2.95- 2.76 (m,4H), 2.76-2.53 (m, 4H), 2.00 (ddd, J = 11.3, 6.0, 3.9 Hz, 1H), 1.39 (s,9H). G-3-3

tert-butyl 15-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro- 1H-1,3-benzodiazol- 5-y]-3,6,9,12-tetraoxapentadecanoate [(M + 18)]⁺ = 581.4 (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 7.08-6.97 (m, 2H), 6.88 (t, J = 4.0 Hz, 1H), 5.34 (dd, J =12.5, 5.4 Hz, 1H), 4.00-3.97 (m, 8H), 3.49-3.46 (m, 7H), 2.99-2.84 (m,1H), 2.78-2.58 (m, 4H), 2.18 (d, J = 5.6 Hz, 1H), 2.06-1.95 (m, 1H),1.81 (h, J = 6.9 Hz, 2H), 1.43 (s, 9H), 1.36 (s, 3H). G-3-4

tert-butyl 2-[2-(2- [3-[3-methyl-1-(1- methyl-2,6- dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]propoxy]ethoxy) ethoxy]acetate 534.4(400 MHz, DMSO-d₆) δ .98 (dd, J = 14.5, 6.0 Hz, 2H), 6.82 (s, 1H), 5.36(d, J = 11.4 Hz, 1H), 4.02-3.90 (m, 2H), 3.54-3.52 (m, 4H), 3.50-3.38(m, 2H), 3.37-3.24 (m, 5H), 2.99 (s, 3H), 2.91 (d, J = 15.3 Hz, 1H),2.77-2.65 (m, 1H), 2.60 (s, 3H), 2.45 (s, 1H), 1.96 (s, 1H), 1.77 (s,2H), 1.41 (s, 1H), 1.39-1.27 (m, 9H). G-3-5

tert-butyl 2-[2-(3- [1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propoxy]ethoxy) acetate [(M +23)]⁺ = 498.2 (400 MHz, DMSO-d₆) δ 11.08 (d, J = 8.4 Hz, 1H), 7.11-6.93(m, 2H), 6.91- 6.82 (m, 1H), 5.34 (dd, J = 12.7, 5.5 Hz, 1H), 4.00 (d, J= 8.9 Hz, 2H), 3.59 (dd, J = 5.9, 3.6 Hz, 2H), 3.53-3.45 (m, 2H), 3.39(s, 5H), 3.00-2.81 (m, 1H), 2.67 (dd, J = 19.5, 11.1 Hz, 3H), 2.00 (d, J= 12.2 Hz, 1H), 1.88-1.72 (m, 2H), 1.45- 1.35 (m, 9H). G-3-6

tert-butyl 2-[2-(3- [3-methyl-1-(1- methyl-2,6- dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]propoxy]ethoxy) acetate [(M + 23)]⁺ =512.3 (400 MHz, DMSO-d₆) δ 6.97 (s, 2H), 6.81 (s, 1H), 5.41 (m, 1H),4.01 (s, 1H), 3.95 (s, 1H), 3.60 (dd, J = 5.9, 3.6 Hz, 1H), 3.54 (s,2H), 3.55-3.49 (m, 1H), 3.52-3.37 (m, 3H), 3.04 (s, 1H), 2.98 (s, 3H),2.67 (q, J = 7.6 Hz, 1H), 2.60 (s, 1H), 2.45 (s, 1H), 1.96 (s, 1H), 1.77(s, 2H), 1.70 (s, 1H), 1.43 (s, 2H), 1.37 (s, 9H). G-3-7

tert-butyl 2-[3-[1- (2,6-dioxpiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5-yl] propoxy]acetate [(M + 18)]⁺ =449.3 (400 MHz, CDCl₃) δ 8.40 (s, 1H), 6.97- 6.87 (m, 2H), 6.73 (d, J =7.9 Hz, 1H), 5.24 (dd, J = 12.6, 5.3 Hz, 1H), 3.98 (s, 2H), 3.56 (t, J =6.3 Hz, 2H), 3.44 (s, 3H), 2.99-2.67 (m, 5H), 2.27-2.19 (m, 1H),2.00-1.91 (m, 2H), 1.48 (s, 9H). G-3-8

tert-butyl 2-[3-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl] propoxy]acetate 509.4 (400 MHz,DMSO-d₆) δ 7.24-7.19 (m, 3H), 7.16 (d, J = 7.8 Hz, 2H), 6.65 (d, J =13.6 Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 4.57-4.37 (m, 2H), 3.95 (s, 2H),3.50-3.35 (m, 4H), 3.31 (s, 1H), 2.61 (q, J = 7.3 Hz, 2H), 2.03 (tdd, J= 14.8, 9.3, 5.4 Hz, 2H), 1.85-1.72 (m, 3H), 1.42 (s, 9H), 1.38 (s, 9H),1.06 (d, J = 6.0 Hz, 3H). G-3-9

tert-butyl 2-([4-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl] but-3-yn-1-yl] oxy)acetate523.4 (400 MHz, DMSO-d₆) δ 7.38-7.01 (m, 5H), 6.63-6.60 (m, 2H),4.50-4.35 (m, 2H), 3.96-3.86 (m, 2H), 3.44-3.39 (m, 4H), 2.57 (q, J =7.3 Hz, 2H), 2.26-1.95 (m, 2H), 1.90-1.69 (m, 2H), 1.60 (q, J = 7.2 Hz,2H), 1.51 (t, J = 7.3 Hz, 2H), 1.44-1.31 (m, 18H), 1.04 (d, J = 6.0 Hz,3H). G-3-10

tert-butyl 5-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl] pent-4-ynoate 493.4 (400 MHz,DMSO-d₆) δ 7.23 (d, J = 8.0 Hz, 2H), 7.20 (s, 1H), 7.13 (d, J = 8.0 Hz,2H), 6.67 (s, 1H), 6.59 (d, J = 9.1 Hz, 1H), 4.49-4.37 (m, 2H),3.43-3.36 (m, 1H), 3.31 (s, 3H), 2.56 (t, J = 7.2 Hz, 2H), 2.20 (t, J =7.0 Hz, 2H), 2.04 (ddd, J = 15.2, 9.6, 5.6 Hz, 1H), 1.60- 1.45 (m, 6H),1.42-1.38 (m, 17H), 1.06 (d, J = 6.0 Hz, 3H). G-3-11

tert-butyl 2-(2-[3- [4-([[(2R,3S)-3-[(tert- butoxycarbonyl)amino-5-carbamoylpentan-2- yl]oxy]methyl)phenyl] propoxy]ethoxy) acetate 553.4(400 MHz, DMSO-d₆) δ 7.23 (d, J = 7.9 2H), 7.15 (d, J = 7.7 Hz, 2H),6.73- 6.56 (m, 2H), 4.50-4.38 (m, 2H), 4.00 (s, 2H), 3.64-3.55 (m, 3H),3.50 (dd, J = 5.9, 3.5 Hz, 2H), 3.40-3.38 (m, 3H), 2.60 (t, J = 7.7 Hz,2H), 2.12-1.97 (m, 2H), 1.83-1.72 (m, 4H), 1.43 (s, 9H), 1.37 (d, J =9.5 Hz, 9H), 1.06 (d, J = 6.0 Hz, 3H). G-3-12

tert-butyl 2-[2-(2-[3-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl] yl]propoxy]ethoxy)ethoxy]acetate 597.5 (400 MHz, DMSO-d₆) δ 7.23 (d, J = 7.9 Hz, 2H), 7.15(d, J = 7.8 Hz, 2H), 6.71- 6.57 (m, 2H), 4.49-4.39 (m, 2H), 3.99 (s,2H), 3.63-3.57 (m, 4H), 3.56-3.52 (m, 4H), 3.48 (dd, J = 5.9, 3.3 Hz,2H), 3.38 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 7.7 Hz, 2H), 2.15-1.96 (m,2H), 1.79-1.76 ( , 4H), 1.42 (s, 9H), 1.38 (d, J = 9.5 , Hz, 9H), 1.06(d, J = 6.0 Hz, 3H). G-3-13

tert-butyl 15-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl]- 3,6,9,12-tetraoxapentadecanoate 641.5 (400 MHz, DMSO-d₆) δ 7.23 (d, J = 7.9 Hz,2H), 7.15 (d, J = 7.8 Hz, 2H), 6.65- 6.62 (m, 2H), 4.51-4.38 (m, 2H),3.98 (d, J = 2.8 Hz, 2H), 3.63-3.45 (m, 7H), 3.43-3.29 (m, 4H), 2.60 (t,J = 7.6 Hz, 2H), 1.82-1.74 (m, 3H), 1.45-1.34 (m, 24H), 1.06 (d, J = 5.9Hz, 3H). G-3-14

tert-butyl 3-[4-([[(2R,3S)- 3-[(tert-butoxycarbonyl) amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl] propanoate 465.5 (400 MHz,CDCl₃) δ 7.25 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 6.52 (s,1H), 5.60-5.45 (m, 1H), 4.90 (d, J = 9.7 Hz, 1H), 4.58 (d, J = 11.5 Hz,1H), 4.39 (d, J = 11.5 Hz, 1H), 3.73- 3.55 (m, 2H), 2.92 (t, J = 7.8 Hz,2H), 2.54 (dd, J = 8.5, 7.2 Hz, 2H), 2.28 (q, J = 6.0, 5.0 Hz, 2H),2.05-1.94 (m, 1H), 1.76-1.64 (m, 1H), 1.46-1.45 (m, 18H), 1.20 (d, J =6.3 Hz, 3H). G-3-15

tert-butyl 5-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] pentanoate 943.4 (400 MHz,DMSO-d₆) δ 7.27-7.17 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 6.67 (s, 1H),6.59 (d, J = 9.1 Hz, 1H), 4.52-4.33 (m, 2H), 3.51-3.35 (m, 2H), 2.56 (t,J = 7.2 Hz, 2H), 2.20 (t, J = 7.0 Hz, 2H), 2.13-1.95 (m, 2H), 1.85-1.72(m, 1H), 1.61-1.45 (m, 5H), 1.40-1.39 (m, 18H), 1.06 (d, J = 6.0 Hz,3H). G-3-16

tert-butyl 2-[2-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] ethoxy]acetate 495.4 (400MHz, DMSO-d₆) δ 7.24-7.20 (m, 5H), 6.68 (s, 1H), 6.61 (d, J = 9.0 Hz,1H), 4.49-4.38 (m, 2H), 3.96 (s, 2H), 3.65 (t, J = 6.9 Hz, 2H), 3.43 (s,2H), 3.42-3.36 (m, 1H), 2.81 (t, J = 6.9 Hz, 2H), 2.10-1.98 (m, 1H),1.79 (s, 1H), 1.43-1.38 (m, 18H), 1.06 (d, J = 6.0 Hz, 3H). G-3-17

tert-butyl 2-(2-[2- [4-([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] ethoxy]ethoxy)acetate 539.4(400 MHz, DMSO-d₆) δ 7.25-7.17 (m, 5H), 6.77-6.53 (m, 2H), 4.50-4.36 (m,2H), 3.97 (s, 2H), 3.63-3.50 (m, 6H), 3.49-3.36 (m, 2H), 2.79 (t, J =7.0 Hz, 2H), 2.13-1.98 (m, 2H), 1.79 (dt, J = 6.7, 3.7 Hz, 1H),1.45-1.36 (m, 18H), 1.06 (d, J = 6.0 Hz, 3H). G-3-18

tert-butyl 2-[2-(2- [2-[4-([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] ethoxy]ethoxy)ethoxy] acetate583.3 (400 MHz, DMSO-d₆) δ 7.26-7.19 (m, 3H), 7.19-7.15 (m, 1H), 6.67(s, 1H), 6.60 (t, J = 8.1 Hz, 1H), 4.51-4.35 (m, 2H), 3.98 (d, J = 6.0Hz, 2H), 3.62-3.53 (m, 4H), 5.53-3.48 (m, 5H), 2.78 (q, J = 6.6 Hz 2H),2.05 (ddp, J = 14.6, 10.5, 4.9 Hz, 2H), 1.78 (s, 1H), 1.63-1.42 (m, 1H),1.45-1.38 (m, 18H), 1.06-1.05 (m, 3H). G-3-19

tert-butyl 14-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2- yl]oxy]methyl)phenyl]- 3,6,9,12-tetraoxapentadecanoate 627.5 (400 MHz, DMSO-d₆) δ 7.23 (d, J = 8.0 Hz,2H), 7.18 (d, J = 8.1 Hz, 2H), 6.71- 6.62 (m, 1H), 6.59 (d, J = 9.1 Hz,1H), 4.52-4.37 (m, 2H), 3.98 (d, J = 2.0 Hz, 2H), 3.63-3.55 (m, 4H),3.55-3.47 (m, 10H), 3.45-3.35 (m, 2H), 2.78 (t, J = 7.0 Hz, 2H),2.17-1.94 (m, 3H), 1.86-1.73 (m, 1H), 1.42-1.38 (m, 18H), 1.05 (d, J =6.0 Hz, 3H). G-3-20

tert-butyl 4-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] butanoate 479.3 (400 MHz,CDCl₃) δ 7.26 (d, J = 7.9 Hz 2H), 7.18 (d, J = 7.8 Hz, 2H), 6.72 (s,1H), 5.62 (s, 1H), 4.92 (d, J = 9.5 Hz, 1H), 4.60 (d, J = 11.4 Hz, 1H),4.39 (d, J = 11.4 Hz, 1H), 3.67 (s, 1H), 3.51 (s, 2H), 2.65 (t, J = 7.6Hz, 2H), 2.30-2.25 (m, 4H), 1.92 (p, J = 7.6 Hz, 2H), 1.46 (d, J = 5.4Hz, 18H), 1.39 (s, 1H), 1.22 (d, J = 6.2 Hz, 3H). G-3-21

methyl 6-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] hexanoate 465.4 (400 MHz,CDCl₃) δ 7.24 (d, J = 7.7 Hz, 2H), 7.16 (d, J = 7.7 Hz, 2H), 6.45 (s,1H), 5.43 (s, 1H), 4.91 (d, J = 9.7 Hz, 1H), 4.58 (d, J = 11.5 Hz, 1H),4.38 (d, J = 11.4 Hz, 1H), 3.68 (s, 3H), 3.62 (q, J = 7.0, 6.1 Hz, 1H),2.62 (t, J = 7.7 Hz, 2H), 2.33-2.29 (m 4H), 1.99 (d, J = 11.6 Hz, 1H),1.69-1.65 (m, 5H), 1.45 (s, 9H), 1.38 (s, 3H), 1.21 (d, J = 6.2 Hz, 3H).G-3-22

methyl 7-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan- 2-yl]oxy]methyl)phenyl] heptanoate [(M + 23)]⁺ =501.3 (400 MHz, CD₃OD) δ 7.28 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.8 Hz,2H), 4.59- 4.44 (m, 2H), 3.66 (s, 3H), 3.57 (dt, J = 7.6, 4.4 Hz, 1H),3.53 (d, J = 6.0 Hz, 1H), 2.62 (t, J = 7.6 Hz, 2H), 2.39-2.21 (m, 4H),2.06-1.92 (m, 1H), 1.65-1.59 (m, 5H), 1.56-1.41 (m, 9H), 1.38-1.34 (m,4H), 1.18 (d, J = 6.1 Hz, 3H). G-3-25

Methyl 5-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-(methylcarbamoyl)pentan- 2-yl]oxy]methyl)phenyl] pentanoate 464.5 (400MHz, CD₃OD) δ 7.10-7.03 (m, 4H), 3.66 (s, 3H), 3.64 (t, J = 6.3 Hz, 1H),3.36 (ddd, J = 7.4, 3.7, 2.6 Hz, 1H), 2.72 (s, 3H), 2.62-2.54 (m, 2H),2.38-2.29 (m, 5H), 2.23 (ddd, J = 13.9, 9.1, 6.0 Hz, 1H), 2.01 (dddd, J= 13.8, 9.6, 6.6, 3.2 Hz, 1H), 1.69- 1.55 (m, 7H), 1.46 (s, 9H), 1.17(d, J = 6.3 Hz, 3H). G-3-26

Methyl 5-[3- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] pentanoate 451.3 (400 MHz,CD₃OD) δ 7.25 (t, J = 7.5 Hz, 1H), 7.22-7.15 (m, 2H), 7.11 (dt, J = 7.4,1.6 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 3.66(s, 3H), 3.64-3.56 (m, 1H), 3.52 (p, J = 6.0 Hz, 1H), 2.69-2.61 (m, 2H),2.41-2.32 (m, 2H), 2.35-2.17 (m, 2H), 1.99 (dddd, J = 13.0, 9.7, 6.7,3.2 Hz, 1H), 1.72-1.57 (m, 5H), 1.46 (s, 9H), 1.18 (d, J = 6.2 Hz, 3H).G-3-27

Methyl 6-[2- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl] hexanoate 465.3 (400 MHz,DMSO-d₆) δ 7.36-7.29 (m, 1H), 7.24-7.11 (m, 4H), 6.71-6.56 (m, 2H),4.54-4.41 (m, 2H), 3.58 (s, 3H), 3.46 (dd,J = 9.3, 6.2 Hz, 2H),2.63-2.56 (m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.13- 1.96 (m, 2H), 1.78(qt, J = 8.0, 4.3 Hz, 1H), 1.55 (m, 5H), 1.39 (s, 9H), 1.35- 1.23 (m,2H), 1.08 (d, J = 5.7 Hz, 3H). G-3-28

tert-Butyl 3-[6- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)naphthalen- 2-yl]propanoate 515.3(400 MHz, CD₃OD) δ 7.78 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H),7.49 (dd, J = 8.5, 1.7 Hz, 1H), 7.38 (dd, J = 8.5, 1.8 Hz, 1H),7.26-7.22 (m, 1H), 7.16 (dt, J = 6.3, 1.8 Hz, 1H), 4.79-4.58 (m, 2H),3.60 (tq,J = 11.6, 6.0, 5.5 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.89-2.79(m, 1H), 2.75 (td, J = 7.3, 1.6 Hz, 1H), 2.65 (t, J = 7.5 Hz, 2H),2.38-2.18 (m, 1H), 2.02 (dt, J = 10.3, 2.8 Hz, 1H), 1.42 (s, 9H), 1.40(s, 9H), 1.22 (d, J = 6.0 Hz, 3H). G-3-29

ethyl 3-[7- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl) naphthalen- 2-yl]propanoate 487.30(400 MHz, DMSO-d₆) δ 7.83-7.81 (m, 2H), 7.76 (s, 1H), 7.68 (s, 1H),7.46- 7.38 (m, 2H), 7.23 (s, 1H), 6.72-6.60 (m, 2H), 4.67-4.59 (m, 2H),4.05 (q, J = 7.1 Hz, 2H), 3.48-3.44 (m, 2H), 3.03- 2.98 (m, 2H),2.73-2.69 (m, 2H), 2.12- 2.05 (m, 2H), 1.90-1.82(m, 1H), 1.58- 1.45 (m,1H), 1.38 (s, 9H), 1.16-1.14 (m, 3H), 1.10 (d, J = 5.8 Hz, 3H) G-3-30

ethyl 3-[6- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)naphthalen- 1-yl]propanoate 487.20Used in the next step without further purification G-3-31

methyl 5-(4- ([[(2S)-2-[(tert- butoxycarbonyl)amino]- 4-carbamoylbutoxy]methyl]phenyl) pentanoate 437.25 (400 MHz, DMSO-d₆) δ 7.26-7.20 (m, 3H),7.15 (d, J = 7.9 Hz, 2H), 6.73-6.63 (m, 2H), 4.41 (s, 2H), 3.37-3.22 (m,4H), 2.60-2.55 (m, 2H), 2.32 (t, J = 6.8 Hz, 2H), 2.12-2.01 (m, 2H),1.80-1.68 (m, 1H), 1.62-1.44 (m, 8H), 1.37 (s, 9H) G-3-32

tert-butyl 3-(2-(2-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5- yl)ethyl)phenyl)propanoate [(M − 1)]⁻ = 490.05 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.27-7.20 (m, 1H), 7.19-7.10 (m, 4H), 7.03 (d, J = 8.0 Hz, 1H), 6.92(dd, J = 8.0, 1.6 Hz, 1H), 5.35 (dd, J = 12.7, 5.4 Hz, 1H), 3.34 (s,3H), 3.00-2.80 (m, 8H), 2.79-2.58 (m, 2H), 2.47-2.44 (m, 2H), 2.11-1.92(m, 1H), 1.37 (s, 9H). G-3-33

methyl 3-[[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl] oxy]methyl)phenyl]methyl]cyclobutane-1-carboxylate 463.27 (400 MHz, CDCl₃) δ 7.52-7.46 (m, 1H),7.23 (t, J = 8.2 Hz, 2H), 7.13 (dd, J = 8.1, 3.9 Hz, 1H), 6.43 (d, J =41.5 Hz, 1H), 5.38 (s, 1H), 4.87 (dd, J = 27.7, 9.8 Hz, 1H), 4.57 (dd, J= 11.7, 7.9 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H), 3.74-3.56 (m, 2H), 3.51(s, 3H), 3.04-2.66 (m, 1H), 2.55-2.22 (m, 3H), 2.12-1.96 (m, 1H),1.79-1.50 (m, 4H), 1.46 (s, 10H), 1.21 (d, J = 6.3 Hz, 3H) G-3-34

methyl 3-(4-[3- [(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutoxy] propyl]phenyl)propanoate 436.55 (400 MHz, CDCl₃) δ7.20-7.19 (m, 1H), 7.16-7.08 (m, 3H), 6.65-6.51 (m, 1H), 5.56 (s, 1H),5.01-4.98 (m, 1H), 4.25 (d, J = 6.3 Hz, 1H), 3.78 (s, 1H), 3.69 (s, 3H),3.53-3.36 (m, 4H), 2.99-2.92 (m, 2H), 2.64 (q, J = 7.3 Hz, 3H),2.37-2.24 (m, 2H), 1.98-1.81 (m, 4H), 1.46 (s, 9H) G-3-35

tert-butyl 2-(4-[[1-(2,6- dioxopiperidine-3-yl)-3- methyl-2-oxo-1,3-benzodiazol-5-yl] methyl]cyclohexyl)acetate [(M − H)]⁻ = 468.20 300 MHz,CDCl₃) δ 8.30 (s, 1H), 6.91- 6.78 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H),5.22 (dd, J = 12.4, 5.3 Hz, 1H), 3.43 (s, 3H), 3.01-2.68 (m, 4H), 2.61(d,J = 7.5 Hz, 1.6 H, cis), 2.53 (d, J = 7.0 Hz, 0.5H, trans), 2.28-2.18(m, 2H), 2.05- 2.01 (m, 1H), 1.76-1.73 (m, 2H), 1.57- 1.43 (m, 16H)G-3-36

methyl 5-[4-([[2R,3S)-3- [(tert-butoxycarbonyl)amino]-5-carbamoylpentan- 2-yl]oxy]methyl)-2- fluorophenyl]pentanoate469.25 (400 MHz, DMSO-d₆) δ 7.26-7.18 (m, 2H), 7.14-7.03 (m, 2H),6.70-6.60 (m, 2H), 4.51-4.39 (m, 2H), 3.58 (s, 3H), 3.49-3.45 (m, 1H),3.43-3.39 (m, 1H), 2.59 (s, 2H), 2.33 (td, J = 6.9, 5.7, 3.1 Hz, 2H),2.13 -1.95 (m, 2H), 1.82-1.70 (m, 1H), 1.60-1.45 (m, 5H), 1.38 (s, 9H),1.06 (d, J = 6.1 Hz, 3H) G-3-37

methyl 5-[4-([[2R,3S)-3- [(tert-butoxycarbonyl)amino]-5-carbamoylpentan- 2-yl]oxy]methyl)-3- fluorophenyl]pentanoate469.30 (400 MHz, DMSO-d₆) δ 7.34 (t, J = 8.0 Hz, 1H), 7.21 (s, 1H),7.05-6.96 (m, 2H), 6.67 (s, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.49 (q, J =8.0 Hz, 2H) 3.58 (s, 3H), 3.47-3.39 (m, 2H), 3.18 (d, J = 5.2 Hz, 1H),2.59 (t, J = 7.1 Hz, 2H), 2.33 (t, J = 7.0 Hz, 2H), 2.10-1.97 (m, 2H),1.84-1.71 (m, 1H), 1.64-1.48 (m, 4H), 1.38 (s, 9H), 1.07 (d, J = 5.7 Hz,3H) G-3-55

methyl 6-[5-[(2S)-2- [(tert-butoxycarbonyl) amino]-4-carbamoyl-butoxy]-2-chlorophenyl] hexanoate 471.30 (400 MHz, DMSO-d₆) δ 7.31-7.24(m, 2H), 6.93-6.88 (m, 1H), 6.86-6.75 (m, 2H), 6.79-6.70 (m, 1H),3.84-3.86 (m, 2H), 3.73-3.69 (m, 1H), 3.59-3.56 (m, 3H), 2.67-2.58 (m,2H), 2.35-2.25 (m, 4H), 2.17-2.07 (m, 2H), 1.63-1.53 (m, 5H), 1.55-1.51(m, 1H), 1.25 (s, 9H G-3-56

methyl 6-[3-[(2S)-2- [(tert-butoxycarbonyl) amino]-4-carbamoyl-butoxy]-4-chlorophenyl] hexanoate 471.25 (400 MHz, DMSO-d₆) δ 7.28 (d, J= 8.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.00-6.98 (m, 1H), 6.8-6.70 (m, 3H),3.94 (d, J = 6.1 Hz, 2H), 3.77 (s, 1H), 3.58-3.35 (m, 3H), 3.32 (s, 1H),2.34-2.25 (m, 5H), 2.13-1.90 (m, 2H), 1.84-1.61 (m, 1H), 1.67-1.54 (m,3H), 1.39 (s, 9H), 1.19- 1.10 (m, 2H) G-3-57

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutoxy]-5-chlorophenyl]hexanoate 471.10 ¹H NMR (400 MHz, DMSO-d₆) δ 7.25 (s, 1H),6.90-6.79 (m, 3H), 6.79-6.70 (m, 2H), 4.48-4.34 (m, 1H), 3.90-3.84 (m,2H), 3.76-3.65 (m, 1H), 3.64-3.59 (m, 1H), 3.58 (s, 3H), 2.31-2.28 (m,2H), 2.15-2.08 (m, 2H), 1.80-1.73 (m, 2H), 1.57-1.53 (m, 4H), 1.38 (s,9H), 1.30-1.26 (m, 2H) G-3-58

6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutoxy]-phenyl]hexanoate 437.35 ¹H NMR (400 MHz, DMSO-d₆) δ 7.27 (s, 1H), 7.17(t, J = 8.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.74 (dd, J = 12.2, 6.3Hz, 4H), 3.86-3.82 (m, 2H), 3.70 (t, J = 7.0 Hz, 1H), 3.58 (s, 3H),2.57-2.51 (m, 2H), 2.30 (t, J = 7.4 Hz, 2H), 2.12-2.08 (m, 2H), 1.81 (s,2H), 1.58-1.54 (m, 4H), 1.40 (s, 9H), 1.32-1.22 (m, 2H) G-3-59

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido] phenyl]hexanoate 450.25 ¹H NMR (300 MHz, DMSO-d₆) δ9.84 (s, 1H), 7.42 (t, J = 1.8 Hz, 2H), 7.18 (d, J = 8.6 Hz, 1H), 7.06(t, J = 7.9 Hz, 2H), 7.04-6.98 (m, 1H), 6.75 (s, 1H), 4.00 (q, J = 7.5Hz, 1H), 3.57 (s, 3H), 3.17 (d, J = 5.3 Hz, 2H), 2.74-2.71 (m, 1H),2.34-2.24 (m, 2H), 2.18-2.10 (m, 1H), 1.60-1.50 (m, 4H), 1.38 (s, 9H),1.33-1.24 (m, 4H) G-3-60

methyl 5-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutoxy]-phenyl]pentanoate 423.10 ¹H NMR (400 MHz, DMSO-d₆) δ 7.26 (s, 1H), 7.17(t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.78-6.69 (m, 4H),3.86-3.82 (m, 2H), 3.74-3.70 (m, 1H), 3.58 (s, 3H), 2.56-2.54 (m, 2H),2.38- 2.24 (m, 4H), 2.19-2.05 (m, 1H), 1.85- 1.80 (m, 1H), 1.59-1.49 (m,4H), 1.39 (s, 9H) G-3-61

tert-butyl N-[(3S,4R)-1- carbamoyl-4-([4-[3-(1- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl- 1-oxobutan-2-yl] carbamoyl]cyclopropyl)propyl] phenyl]methoxy)pentan- 3-yl]carbamate 875.55 ¹H NMR(400 MHz, Methanol-d₄) δ 8.89 (s, 1H), 7.60-7.42 (m, 4H), 7.30- 7.22 (m,2H), 7.18 (d, J = 8.1 Hz, 2H), 4.75-4.68 (m, 1H), 4.65-4.58 (m, 1H),4.60-4.53 (m, 1H), 4.51 (s, 2H), 4.46 (d, J = 11.4 Hz, 1H), 4.36 (d, J =15.5 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.85- 3.72 (m, 1H), 3.57 (s,1H), 3.62-3.44 (m, 1H), 2.70-2.61 (m, 2H), 2.30-2.22 (m, 1H), 2.25 (s,1H), 2.26-2.16 (m, 1H), 2.18-2.05 (m, 1H), 1.96 (s, 1H), 1.94 (s, 3H),1.85-1.76 (m, 3H), 1.62 (s, 1H), 1.45 (s, 9H), 1.38-1.26 (m, 2H),1.20-1.09 (m, 4H), 1.03 (s, 9H), 0.70- 0.59 (m, 2H) G-3-62

methyl 5-[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy] methyl)-2-methylphenyl] pentanoate 465.30 ¹HNMR (400 MHz, DMSO-d₆) δ 7.21 (s, 1H), 7.11-7.03 (m, 3H), 6.67 (s, 1H),6.59 (d, J = 9.2 Hz, 1H), 4.43-4.35 (m, 2H), 3.59 (s, 3H), 3.48-3.37 (m,1H), 2.56-2.54 (m, 3H), 2.35 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H),2.12-1.97 (m, 2H), 1.83-1.76 (m, 1H), 1.63-1.42 (m, 5H), 1.39 (s, 9H),1.05 (d, J = 6.0 Hz, 3H) G-3-63

methyl 5-[4-([[2R,3S)-3- [(tert-butoxycarbonyl)amino]-5-carbamoylpentan- 2-yl]oxy]methyl)-3- fluorophenyl]pentanoate469.30 ¹H NMR (400 MHz, DMSO-d₆) δ 7.34 (t, J = 7.8 Hz, 1H), 7.21 (s,1H), 7.04- 6.96 (m, 2H), 6.68 (s, 1H), 6.60 (d, J = 8.6 Hz, 1H),4.57-4.37 (m, 2H), 3.58 (s, 3H), 3.45-3.38 (m, 2H), 2.58 (t, J = 7.1 Hz,2H), 2.33 (t, J = 7.0 Hz, 2H), 2.12- 1.92 (m, 2H), 1.81-1.74 (m, 1H),1.63- 1.47 (m, 4H), 1.38 (s, 9H), 1.35 (s, 1H), 1.06 (d, J = 5.4 Hz, 3H)G-3-64

methyl 5-[4-([[2R,3S)-3- [(tert-butoxycarbonyl)amino]-5-carbamoylpentan- 2-yl]oxy]methyl)-3- methylphenyl]pentanoate465.40 ¹H NMR (400 MHz, Methanol-d₄) δ 7.22 (d, J = 7.6 Hz, 1H),7.03-6.95 (m, 2H), 4.61-4.45 (m, 2H), 3.66 (d, J = 3.1 Hz, 4H),3.61-3.50 (m, 2H), 2.61-2.56 (m, 2H), 2.37-2.31 (m, 5H), 2.28-2.17 (m,2H), 2.01-1.92 (m, 1H), 1.65-1.61 (m, 4H), 1.45 (s, 9H), 1.19 (d, J =6.0 Hz, 3H) G-3-65

methyl 5-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbuyoxy]-2-fluoro-5-methylphenyl] pentanoate 455.25 (300 MHz, DMSO-d₆) δ 7.24 (s,1H), 6.85-6.74 (m, 2H), 6.71 (s, 1H), 6.64- 6.55 (m, 1H), 3.88 (d, J =6.0 Hz, 2H), 3.77-3.67 (m, 1H), 3.57 (s, 3H), 2.61- 2.51 (m, 2H), 2.22(s, 3H), 2.16-2.06 (m, 2H), 1.60-1.44 (m, 8H), 1.37 (s, 9H) G-3-66

methyl 5-[4-[(4R)-4-[(tert- butoxycarbonyl)amino]-6-carbamoylhexyl]phenyl] pentanoate 435.30 (400 MHz, DMSO-d₆) δ 7.21 (s,1H), 7.10-7.06 (m, 4H), 6.68 (s, 1H), 6.59 (d, J = 9.0 Hz, 1H), 3.58 (s,3H), 3.41-3.34 (m, 1H), 2.61-2.56 (m, 2H), 2.50-2.47 (m, 1H), 2.32-2.32(m, 2H), 2.02 (t, J = 7.9 Hz, 2H), 1.64-1.48 (m, 11H), 1.38 (s, 9H)G-3-67

methyl 6-[6-[(1S)-3- carbamoyl-1- [(2-methylpropane-2-sulfinyl)amino]propyl] pyridin-3-yl]hexanoate 412.30 (400 MHz, DMSO-d₆)δ 8.39-8.37 (d, J = 2.3 Hz, 1H), 7.63-7.61 (dd, J = 8.0, 2.3 Hz, 1H),7.33-7.17 (m, 2H), 6.78 (s, 1H), 5.57-5.66 (d, J = 5.2 Hz, 1H),4.27-4.22 (m, 1H), 3.57 (s, 3H), 2.71- 2.67 (t, J = 7.7 Hz, 2H),2.31-2.28 (t, J = 7.4 Hz, 2H), 2.17-2.10 (m, 1H), 2.08-1.97 (m, 2H),1.93-1.80 (m, 1H), 1.70-1.62 (m, 2H), 1.60-1.52 (m, 2H), 1.38-1.21 (m,2H), 1.08 (s, 9H) G-3-68

methyl 5-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutoxy]-2-chlorophenyl]pentanoate 457.15 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H), 7.20(t, J = 7.9 Hz, 1H), 6.98 (dd, J = 8.4, 1.4 Hz, 1H), 6.90 (dd, J = 7.7,1.3 Hz, 1H) 6.81 (d, J = 8.5 Hz, 1H), 6.77- 6.72 (m, 1H), 3.92 (d, J =6.1 Hz, 2H), 3.82-3.72 (m, 1H), 3.58 (s, 3H), 2.69 (s, 2H), 2.38-2.29(m, 2H), 2.23-2.05 (m, 2H), 1.91-1.78 (m, 1H), 1.69-1.59 (m, 1H),1.59-1.51 (m, 4H), 1.39 (s, 9H) G-3-69

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutoxy]-5-chloro-2-fluorophenyl] hexanoste 489.20 (300 MHz, DMSO-d₆) δ 7.28 (s,1H), 7.13-7.11 (m, 1H), 6.93-6.91 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H),6.75 (s, 1H), 4.02-3.86 (m, 2H), 3.75-3.73 (m, 1H), 3.59 (s, 3H), 2.58(d, J = 7.5 Hz, 2H), 2.16-2.14 (m, 2H), 1.83-1.71 (m, 1H), 1.58-1.51 (m,9H), 1.39 (s, 9H) G-3-70

3-(5-[1,4-dioxaspiro[4.5] decan-8-ylmethyl]-3- methyl-2-oxo-1,3-benzodiazol-1-yl) piperidine-2,6-dione 414.20 (300 MHz, DMSO-d₆) δ7.04-7.00 (m, 2H), 6.85-6.82 (m, 1H), 5.38-5.34 (m, 1H), 3.85-3.83 (m,4H), 3.21-3.17 (m, 2H), 2.92-2.90 (m, 1H), 2.79-2.57 (m, 3H), 2.06-1.97(m, 1H), 1.65-1.60 (m, 6H), 1.42-1.39 (m, 2H), 1.21 (s, 3H) G-3-71

methyl 5-(3-[2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutanamido]-2-chlorophenyl)pentanoate 470.15 (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.74(d, J = 8.0 Hz, 1H), 7.68-7.61 (m, 1H), 7.65-7.55 (m, 1H), 7.33-7.22 (m,1H), 7.13 (dd, J = 7.6, 1.6 Hz, 1H), 6.81 (s, 1H), 4.15-4.09 (m, 1H),3.58 (s, 3H), 2.72 (d, J = 13.7 Hz, 1H),2.39-2.31 (m, 2H), 2.19 (s, 3H),1.88 (s, 3H), 1.58 (d, J = 3.6 Hz, 3H), 1.41 (s, 9H) G-3-72

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido]- 2-chlorophenyl] hexanoate 484.25 (300 MHz,DMSO-d₆) δ 9.32 (s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.31-7.24 (m, 1H),7.14 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 4.11 (q, J = 5.2 Hz, 1H), 3.59(s, 3H), 3.18 (d, J = 5.3 Hz, 2H), 2.77-2.66 (m, 2H), 2.32 (t, J = 7.3Hz, 2H), 2.23- 2.18 (m, 2H), 2.11-1.71 (m, 2H), 1.63- 1.55 (m, 5H), 1.42(s, 9H), 1.37-1.25 (m, 1H) G-3-73

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido]-2- fluorophenyl] hexanoate [(M − 1)]⁻ = 466.20 (300MHz, DMSO-d₆) δ 9.58 (s, 1H), 7.77-7.73 (m, 1H), 7.69-7.51 (m, 4H), 7.30(s, 1H), 7.14-7.01 (m, 3H), 6.80 (s, 1H), 4.18-4.14 (m, 1H), 3.18 (d, J= 5.2 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 2.31 (t, J = 7.3 Hz, 2H),2.22-2.14 (m, 1H), 2.04-1.67 (m, 1H), 1.62-1.52 (m, 4H), 1.40 (s, 9H),1.37-1.22 (m, 2H) G-3-74

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutoxy]-2-fluoro-6-methylphenyl] hexanoate 469.15 (400 MHz, DMSO-d₆) δ 7.26 (s,1H), 6.92-6.84 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H),3.91-3.84 (m, 2H), 3.79-3.62 (m, 1H), 3.58 (s, 3H), 2.56 (s, 2H), 2.30(t, J = 7.4 Hz, 2H), 2.21 (s, 3H), 2.18-2.04 (m, 2H), 1.87-1.74 (m, 1H),1.65-1.51 (m, 3H), 1.48-1.44 (m, 2H), 1.39 (s, 9H), 1.37-1.26 (m, 2H)G-3-75

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutoxy]-2,6- difluorophenyl]hexanoate 473.10 (400 MHz, DMSO-d₆)δ 7.26 (s, 1H), 7.06-7.02 (m, 1H), 6.98-6.94 (m, 1H), 6.83 (d, J = 8.4Hz, 1H), 6.74 (s, 1H), 3.93-3.89 (m, 2H), 3.78-3.65 (m, 1H), 3.57 (s,3H), 2.62-2.58 (m, 2H), 2.31- 2.27 (m, 2H), 2.21-2.05 (m, 2H), 1.84-1.80 (m, 1H), 1.63-1.46 (m, 5H), 1.38 (s, 9H), 1.33-1.20 (m, 2H) G-3-76

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido]- 5-chlorophenyl]hexanoate 484.15 (300 MHz, DMSO-d₆)δ 10.08 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.28 (s, 2H), 7.06 (d, J =7.5 Hz, 1H), 6.95 (d, J = 1.7 Hz, 1H), 6.76 (s, 1H), 4.03-3.95 (m, 1H),3.56 (s, 3H), 2.54 (d, J = 7.6 Hz, 2H), 2.29 (t, J = 7.3 Hz, 2H),2.22-2.06 (m, 2H), 1.91-1.68 (m, 2H), 1.37 (s, 9H), 1.35-1.26 (m, 6H)G-3-77

Methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido]- 5-methylphenyl]hexanoate 464.20 (300 MHz, DMSO-d₆)δ 9.78 (s, 1H), 7.32-7.26 (m, 2H), 7.22 (s, 1H), 7.00 (d, J = 7.7 Hz,1H), 6.78 (s, 1H), 6.71 (s, 1H), 4.02 (d, J = 6.8 Hz, 1H), 3.59 (s, 3H),2.31 (t, J = 7.4 Hz, 2H), 2.25 (s, 3H), 2.20-2.08 (m, 2H), 1.97-1.69 (m,3H), 1.56 (pd, J = 7.4, 3.3 Hz, 5H), 1.40 (s, 9H), 1.37-1.23 (m, 2H)G-3-78

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido]- 2-methylphenyl]hexanoate 464.25 (300 MHz, DMSO-d₆)δ 9.27 (d, J = 5.3 Hz, 1H), 7.32 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H),7.09-6.99 (m, 3H), 6.80 (s, 1H), 4.13-4.04 (m, 1H), 3.60 (s, 3H), 2.60(t, J = 7.7 Hz, 2H), 2.32 (t, J = 7.4 Hz, 2H), 2.20 (d, J = 5.3 Hz, 2H),2.12 (s, 3H), 2.06-1.74 (m, 2H), 1.64-1.47 (m, 3H), 1.42 (s, 9H),1.38-1.31 (m, 3H) G-3-79

methyl 5-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4- carbamoylbutoxy]-2-fluorophenyl]pentanoate 441.20 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H),7.04-6.97 (m, 2H), 6.85-6.81 (m, 2H), 6.74 (s, 1H), 4.11 (q, J = 5.3 Hz,1H), 3.91 (d, J = 6.1 Hz, 2H), 3.76-3.72 (m, 1H), 3.58 (s, 3H), 2.58 (t,J = 7.1 Hz, 2H), 2.36-2.30 (m, 2H), 2.18-2.07 (m, 2H), 1.87-1.77 (m,1H), 1.57-1.51 (m, 4H), 1.39 (s, 9H) G-3-80

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido]- 5-fluorophenyl]hexanoate 468.20 (400 MHz, DMSO-d₆)δ 10.13 (s, 1H), 7.45-7.31 (m, 1H), 7.31 (s, 1H), 7.16 (t, J = 1.6 Hz,1H), 7.09 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.73 (dt, J = 9.8, 1.9 Hz,1H), 4.04-4.02 (m, 1H), 3.58 (s, 3H), 2.56-2.54 (m, 2H), 2.30 (t, J =7.4 Hz, 2H), 2.24-2.06 (m, 2H), 1.97-1.73 (m, 2H), 1.60-1.52 (m, 4H),1.39 (s, 9H), 1.32-1.26 (m, 2H) G-3-81

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutyl]-amino)-2- fluorophenyl]hexanoate 454.20 (400 MHz,DMSO-d₆) δ 7.25 (s, 1H), 6.90-6.76 (m, 2H), 6.72 (s, 1H), 6.60 (t, J =8.2 Hz, 1H), 6.41 (t, J = 7.1 Hz, 1H), 5.23 (s, 1H), 3.60-3.56 (m, 4H),3.18 (s, 1H), 3.07-3.03 (m, 3H), 2.52 (d, J = 15.5 Hz, 1H), 2.29 (t, J =7.4 Hz, 2H), 2.16-1.98 (m, 2H), 1.91- 1.87 (m, 1H), 1.79-1.75 (m, 1H),1.68-1.64 (m, 1H), 1.63-1.47 (m, 4H), 1.27 (s, 9H) G-3-82

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutoxy]-2-fluoro- 5-methylphenyl]hexanoate 469.30 (400 MHz,DMSO-d₆) δ 7.27 (s, 1H), 6.86-6.76 (m, 2H), 6.74 (s, 1H), 6.61 (d, J =6.0 Hz, 1H), 3.93-3.84 (m, 2H), 3.75-3.69 (m, 1H), 2.61-2.52 (m, 2H),2.29 (t, J = 7.4 Hz, 2H), 2.23 (s, 3H), 2.17-2.05 (m, 2H), 1.88-1.75 (m,1H), 1.65-1.47 (m, 6H), 1.39 (s, 9H), 1.34- 1.22 (m, 4H) G-3-83

methyl 6-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutoxy]-2,5- difluorophenyl]hexanoate 473.20 (400 MHz, CD3OD) δ6.78-6.72 (m, 1H), 6.58-6.51 (m, 1H), 3.98 (d, J = 5.5 Hz, 2H), 3.88 (s,1H), 3.64 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H), 2.37-2.27 (m, 4H),2.03-1.94 (m, 3H), 1.84-1.77 (m, 1H), 1.71-1.55 (m, 4H), 1.44 (s, 9H)G-3-84

methyl 6-[2-[(1S)-3- carbamoyl-1-[(2-methyl- propane-2-sulfinyl)amino]propyl]pyridin-4-yl] hexanoate 412.20 (400 MHz, DMSO-d₆) δ 8.40 (d, J =5.1 Hz, 1H), 7.29 (s, 1H), 7.21-7.09 (m, 2H), 6.80 (s, 1H), 5.74 (d, J =5.5 Hz, 1H), 4.25-4.20 (m, 1H), 3.58 (s, 3H), 2.71-2.67 (m, 2H),2.30-2.27 (t, J = 7.4 Hz, 2H), 2.16-2.01 (m, 3H), 1.93-1.78 (m, 1H),1.69-1.62 (m, 2H), 1.59-1.51 (p, J = 7.5 Hz, 2H), 1.34-1.23 (m, 2H),1.09 (s, 9H) G-3-85

methyl 5-[3-[(2S)-2-[(tert- butoxycarbonyl)amino]-4-carbamoylbutanamido] phenyl]pentanoate 436.25 (300 MHz, DMSO-d₆) δ 9.88(s, 1H), 7.68-7.64 (m, 2H), 7.44 (s, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.89(d, J = 7.5 Hz, 1H), 3.59 (s, 3H), 3.19 (d, J = 5.3 Hz, 2H), 2.36-2.32(m, 2H), 1.61-1.55 (m, 5H), 1.40 (s, 9H), 1.28-1.26 (m, 5H)

Tert-butyl 2-[4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]acetate(Intermediate G-3-23)

To a stirred solution of tert-butylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(800 mg, 1.90 mmol) and tert-butyl 3-bromopropanoate (806 mg, 3.90 mmol)in THF (40.0 mL) were added Pd₂(dba)₃.CHCl₃ (399 mg, 0.39 mmol) andX-Phos (368 mg, 0.77 mmol) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 16 hours at 65° C.under nitrogen atmosphere. The resulting mixture was cooled down to roomtemperature and concentrated under reduced pressure. The residue waspurified by reversed phase flash chromatography with the followingconditions (Column: Spherical C18, 20-40 um, 330 g; Mobile Phase A:water (plus 0.05% AcOH), Mobile Phase B: ACN; Flow rate: 45 mL/min;Gradient (B %): 5%˜45%, 4 min; 45%˜75%, 30 min; Detector: UV 254 nm. Thefractions containing the desired product were collected at 70% B andconcentrated under reduced pressure to afford the title compound as abrown oil (270 mg, 31%): ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.20 (m, 4H),6.50 (s, 1H), 4.92 (d, J=9.6 Hz, 1H), 4.59 (d, J=11.6 Hz, 1H), 4.40 (d,J=11.6 Hz, 1H), 3.64 (ddd, J=16.5, 9.7, 3.2 Hz, 2H), 3.53 (s, 2H),2.36-2.21 (m, 2H), 2.13-1.95 (m, 1H), 1.46-1.45 (m, 18H), 1.21 (d, J=6.3Hz, 3H); MS (ESI, m/z): [(M+1)]⁺=451.35.

Tert-butyl2-[2-(2-[2-[4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]ethoxy]ethoxy)ethoxy]acetate(Intermediate G-3-24)

To a stirred mixture of tert-butylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(400 mg, 0.96 mmol) in DMSO (4.00 mL) were added MeOH (13.0 mL),Pd(dppf)Cl₂ (70.5 mg, 0.096 mmol) and TEA (13.0 mL) at 25° C. under CO(1.5 atm.) atmosphere. The resulting mixture was purged with CO forthree times and stirred for additional 16 hours at 80° C. The resultingmixture was cooled down to room temperature and concentrated underreduced pressure. The residue was purified by reversed phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 40 g; Eluent A: water (plus 10 mmol/L AcOH); Eluent B: ACN;Gradient: 35%-55% B in 20 min; Flow rate: 30 mL/min; Detector: UV220/200 nm; desired fractions were collected at 55% B and concentratedunder reduced pressure to afford the title compound as a yellow solid(215 mg, 57%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.96-7.89 (m, 2H), 7.48 (d,J=8.2 Hz, 2H), 7.22 (s, 1H), 6.71-6.62 (m, 2H), 4.63-4.52 (m, 2H), 3.85(s, 3H), 3.45 (dd, J=14.4, 8.3 Hz, 2H), 2.12-2.00 (m, 1H), 1.93-1.70 (m,1H), 1.54-1.45 (m, 1H), 1.38 (s, 9H), 1.09 (d, J=6.0 Hz, 3H); MS (ESI,m/z): [(M+1)]⁺=395.30.

Tert-butyl1-[4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]piperidine-4-carboxylate(Intermediate G-3-38)

To a stirred solution of tert-butylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(500 mg, 1.21 mmol) and tert-butyl piperidine-4-carboxylatehydrochloride (320 mg, 1.45 mmol) in DMF (10.0 mL) was added XPhos Pd G₃(153 mg, 0.18 mmol) and K₃PO₄ (1022 mg, 4.82 mmol) at 25° C. undernitrogen atmosphere. The final reaction mixture was irradiated withmicrowave radiation for 2 h at 130° C. The mixture was allowed to cooldown to room temperature. The reaction was purified by reverse phaseflash chromatography with the following conditions: Column: SphericalC¹⁸ Column, 20-40 um, 120 g; Mobile Phase A: water (plus 0.05% NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in25 min; Detector: UV 254/220 nm. The fractions containing the desiredproduct were collected at 40% B to afford the title compound as a whitesolid (160 mg, 26%): ¹H NMR (400 MHz, CD₃OD) δ 7.27-7.23 (m, 2H),6.99-6.94 (m, 2H), 4.53-4.40 (m, 2H), 3.63 (dt, J=12.5, 3.8 Hz, 2H),3.56-3.54 (m, 1H), 3.50 (t, J=5.9 Hz, 1H), 2.82-2.74 (m, 2H), 2.40-2.38(m, 1H), 2.27-2.25 (m, 2H), 2.02-1.93 (m, 3H), 1.80-1.76 (m, 2H),1.62-1.60 (m, 1H), 1.48-1.46 (m, 18H), 1.16 (d, J=6.2 Hz, 3H); LC/MS(ESI, m/z): [(M+Na)]⁺=542.30.

The intermediates in Table 29 were prepared according to the aboveprocedure to prepare Intermediate G-3-38.

TABLE 29 Characterization data for intermediates prepared according toabove. Chemical Intermediate Structure Name MS: [(M + 1)]⁺ ¹H-NMR G-3-39

methyl 2-[1-[4- ([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]piperidin- 4-yl]acetate 492.45(400 MHz, CD₃OD) δ 7.27- 7.22 (m, 2H), 6.99-6.94 (m, 2H), 4.52-4.40 (m,2H), 3.69 (s, 3H), 3.66 (d, J = 3.2 Hz, 1H), 3.59-3.53 (m, 1H), 3.51-3.46 (m, 1H), 2.75-2.68 (m, 2H), 2.33 (d, J = 7.0 Hz, 2H), 2.29-2.20 (m,2H), 2.01-1.90 (m, 2H), 1.86-1.81 (m, 2H), 1.63-1.58 (m, 1H), 1.45 (s,9H), 1.44-1.36 (m, 3H), 1.19- 1.12 (m, J = 6.2 Hz, 3H) G-3-40

ethyl 3-[1-[4- ([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]piperidin- 4-yl]propanoate520.05 Used in the next step without further purification G-3-41

1-methyl-6- (piperazin-1- yl)-3H-1,3- benzodiazol-2- one 233.10 (400MHz, DMSO-d₆) δ 10.54 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H),6.57 (d, J = 8.5 Hz, 1H), 3.24 (s, 3H), 3.04-2.97 (m, 4H), 2.94- 2.86(m, 4H), 1.42-1.37 (m, 1H)

Ethyl2-[4′-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)-[1,1′-biphenyl]-3-yl]acetate(Intermediate G-3-42)

To a stirred solution of ethyl2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (0.70g, 2.41 mmol) and tert-butylN-[(3S,4R)-4-[(4-bromophenyl)methoxy]-1-carbamoylpentan-3-yl]carbamate(1.00 g, 2.41 mmol) in dioxane (10.0 mL) and H₂O (1.00 mL) were addedK₂CO₃ (0.67 g, 4.85 mmol) and Pd(PPh₃)₄ (0.22 g, 0.19 mmol, 0.08 equiv)at 25° C. The resulting mixture was stirred for additional 3 h at 90° C.under nitrogen atmosphere. The resulting solution was cooled down toroom temperature and was purified by reverse phase flash chromatographywith the following conditions: Column: Spherical C¹⁸ Column, 20-40 um,120 g; Mobile Phase A: water (plus 0.1% HOAc), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient: 50% B to 70% B in 25 min; Detector: UV254/220 nm. The fractions containing the desired product were collectedat 60% B and concentrated under reduced pressure to afford the titlecompound as a black solid (390 mg, 32%): ¹H NMR (400 MHz, DMSO-d₆) δ7.62 (d, J=8.2 Hz, 2H), 7.56 (dd, J=7.0, 1.4 Hz, 2H), 7.42 (t, J=8.3 Hz,3H), 7.29-7.20 (m, 2H), 6.72-6.61 (m, 2H), 4.58-4.49 (m, 2H), 4.11 (q,J=7.1 Hz, 2H), 3.75 (s, 2H), 3.47 (m, J=11.7, 6.1 Hz, 2H), 2.12-2.03 (m,2H), 1.85-1.81 (m, 1H), 1.56-1.45 (m, 1H), 1.40 (s, 9H), 1.21 (t, J=7.1Hz, 3H), 1.10 (d, J=5.9 Hz, 3H); LC/MS (ESI, m/z): [(M+1)]⁺=499.30.

The intermediates in Table 30 were prepared according to the aboveprocedure to prepare Intermediate G-3-42.

TABLE 30 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-3-43

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- ethenylphenyl)methoxy]pentan-3- yl]carbamate 263.10 (400 MHz, DMSO-d₆) δ 7.43 (d, J =8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.27-7.19 (m, 1H), 6.76-6.61 (m,3H), 5.82 (dd, J = 17.7, 1.1 Hz, 1H), 5.24 (dd, J = 11.0, 1.0 Hz, 1H),4.54-4.39 (m, 2H), 3.48-3.37 (m, 2H), 2.12-1.97 (m, 2H), 1.83-1.77 (m,1H), 1.52-1.44 (m, 1H), 1.38 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H)

Tert-butyl2-(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]piperidin-1-yl)acetate(Intermediate G-3-44)

To a stirred mixture of3-[3-methyl-2-oxo-5-(piperidin-4-ylmethyl)-1,3-benzodiazol-1-yl]piperidine-2,6-dionetrifluoroacetate (1.30 g, 0.003 mmol) and tert-butyl 2-bromoacetate(0.67 g, 3.44 mmol) in acetone (30.0 mL) was added K₂CO₃ (0.99 g, 7.16mmol) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 16 h at room temperature under nitrogenatmosphere. The resulting mixture was filtered. The filtered cake waswashed with DCM (3×5.00 mL). The combined filtrates was concentratedunder reduced pressure. The residue was purified by reverse phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 330 g; Eluent A: water (plus 10 mmol/L FA); Eluent B: ACN;Gradient: 25%-50% B in 25 min; Flow rate: 80 mL/min; Detector: UV220/254 nm; desired fractions were collected at 45% B and concentratedunder reduced pressure to afford the title compound as a light yellowsolid (1.0 g, 70%): ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 6.87-6.79(m, 2H), 6.74 (d, J=8.0 Hz, 1H), 5.23 (dd, J=12.7, 5.4 Hz, 1H), 3.44 (s,3H), 3.29 (d, J=10.8 Hz, 2H), 2.99-2.59 (m, 8H), 2.26-2.18 (m, 2H),1.78-1.54 (m, 5H), 1.47 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=471.15.

The intermediates in Table 31 were prepared according to the aboveprocedure to prepare Intermediate G-3-44.

TABLE 31 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-3-45

methyl 2-(4-[[4- ([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]methyl] piperidin-1-yl)acetate506.35 (400 MHz, DMSO-d₆) δ 7.28-7.19 (m, 3H), 7.11 (d, J = 7.8 Hz, 2H),6.68 (s, 1H), 6.61 (d, J = 9.0 Hz, 1H), 4.52-4.38 (m, 2H), 3.59 (s, 3H),3.44-3.40 (m, 2H), 3.17 (s, 2H), 2.78 (dt, J = 11.3, 3.4 Hz, 2H), 2.48(d, J = 6.8 Hz, 2H), 2.19-1.94 (m, 4H), 1.81- 1.78 (m, 1H), 1.52-1.48(m, 3H), 1.40 (s, 9H), 1.22-1.14 (m, 2H), 1.06 (d, J = 6.0 Hz, 3H)

Tert-butyl2-(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]piperazin-1-yl)acetate(Intermediate G-3-46)

To a stirred mixture of1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazole-5-carbaldehyde(500 mg, 1.74 mmol) and tert-butyl 2-(piperazin-1-yl)acetate (697.18 mg,3.481 mmol) in DCM (10.00 mL) was added TEA (352.24 mg, 3.481 mmol) atroom temperature under nitrogen atmosphere. To the above mixture wereadded NaBH₃CN (218.75 mg, 3.481 mmol) and AcOH (0.50 mL) at roomtemperature. The resulting mixture was stirred for overnight at roomtemperature. The resulting mixture was concentrated under reducedpressure. The residue product was purified by reverse phase flashchromatography with the following conditions: Column: Spherical C18,20˜40 um, 330 g; Mobile Phase A: water (plus 0.05% TFA), Mobile Phase B:ACN; Flow rate: 80 mL/min; Gradient B %: 30%˜65%, 30 min; Detector: UV254/220 nm; Rt: 35 min to afford the title compound as a light yellowsolid (200 mg, 240): ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 6.87-6.79(m, 2H), 6.74 (d, J=8.0 Hz, 1H), 5.23 (dd, J=12.7, 5.4 Hz, 1H), 4.07 (s,2H), 3.44 (s, 3H), 3.30-3.26 (m, 2H), 2.99-2.59 (m, 11H), 2.26-2.18 (m,1H), 1.47 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=472.15

The intermediates in Table 32 were prepared according to the aboveprocedure to prepare Intermediate G-3-46.

TABLE 32 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-3-47

tert-butyl 4-[4-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]piperidin-1- yl]butanoate 485.20 (400 MHz, DMSO-d₆) δ11.10 (s, 1H), 7.14-6.99 (m, 2H), 6.92 (d, J = 8.1 Hz, 1H), 5.36 (dd, J= 12.7, 5.5 Hz, 1H), 3.56- 3.48 (m, 2H), 3.35 (s, 3H), 3.14-2.78 (m,4H), 2.76-2.56 (m, 3H), 2.33 (dd, J = 7.5, 3.0 Hz, 2H), 2.22 (t, J = 7.5Hz, 2H), 2.07-1.84 (m, 6H), 1.43 (s, 9H) G-3-48

tert-butyl 6-[[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]amino]hexanoate 445.25 (400 MHz, CDCl₃) δ 8.11 (s,1H), 6.62 (d, J = 8.4 Hz, 1H), 6.39-6.30 (m, 2H), 5.18 (dd, J = 12.7,5.4 Hz, 1H), 3.40 (s, 3H), 3.14 (t, J = 7.1 Hz, 2H), 2.99-2.90 (m, 1H),2.89- 2.77 (m, 1H), 2.72-2.68 (m, 1H), 2.30-2.18 (m, 3H), 2.03 (s, 3H),1.7- 1.62 (m, 1H), 1.69-1.65 (m, 3H), 1.47 (s, 9H) G-3-49

tert-butyl 4-[4- (3-methyl-2-oxo- 1H-1,3- benzodiazol-5- yl)piperazin-1-yl]butanoate 375.20 (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 6.83 (d, J = 8.4Hz, 1H), 6.75 (s, 1H), 6.59 (d, J = 8.5 Hz, 1H), 3.24 (s, 3H), 3.16-3.08(m, 4H), 2.75-2.68 (m, 4H), 2.26 (t, J = 7.2 Hz, 2H), 1.96-1.89 (m, 2H),1.78-1.69 (m, 2H), 1.41 (s, 9H)

Tert-butyl3-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]piperidin-1-yl]propanoate(Intermediate G-3-50)

To a stirred solution of3-[3-methyl-2-oxo-5-(piperidin-4-yl)-1,3-benzodiazol-1-yl]piperidine-2,6-dione;trifluoroacetic acid (600 mg, 1.32 mmol) and tert-butyl prop-2-enoate(350.83 mg, 2.737 mmol) in EtOH (15.00 mL) was added TEA (415.46 mg,4.106 mmol) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 2 h at 80° C. under nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure to afford thetitle compound as a yellow oil (600 mg, 79%): ¹H NMR (400 MHz, DMSO-d₄)δ 11.09 (s, 1H), 7.13-6.99 (m, 2H), 6.98-6.84 (m, 1H), 5.35 (dd, J=12.7,5.4 Hz, 1H), 3.45 (q, J=7.1 Hz, 1H), 3.34 (s, 3H), 2.98-2.86 (m, 3H),2.80-2.53 (m, 5H), 2.07-1.69 (m, 8H), 1.43 (s, 9H); LC/MS (ESI, m/z):[(M+1)]⁺=471.15.

The intermediates in Table 33 were prepared according to the aboveprocedure to prepare Intermediate G-3-50.

TABLE 33 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-3-51

tert-butyl 3-[4- (3-methyl-2-oxo- 1H-1,3- benzodiazol-5- yl)piperazin-1-yl]propanoate 361.15 (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 6.81 (d, J =8.4 Hz, 1H), 6.74 (s, 1H), 6.57 (d, J = 8.5 Hz, 1H), 3.24 (s, 3H),3.08-3.02 (m, 4H), 2.59 (t, J = 7.1 Hz, 2H), 2.60-2.54 (m, 2H),2.52-2.46 (m, 2H), 2.39 (t, J = 7.1 Hz, 2H), 1.40 (s, 9H)

Tert-butyl2-[(1s,4s)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetate(Intermediate G-3-52) and tert-butyl2-[(1r,4r)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetate(Intermediate G-3-53)

A mixture of tert-butyl2-(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl)acetate(13.00 g) was separated by SFC with the following conditions: Column:CHIRAL ART Amylose-SC, 5×25 cm (5 um); Mobile Phase A: CO₂, Mobile PhaseB: IPA:MeCN=1:1; Flow rate: 200 mL/min; Gradient: 50% B; Detector: UV220/254 nm; RTL: 5.28 min; RT2: 10.29 min; The first peak fractions(RT1: 5.28 min) were collected and concentrated in vacuum to givecompound 1 (S configuration, assumed) 5.3 g. The second peak fractions(RT2: 10.29 min) were collected and concentrated in vacuum to givecompound 2 (R configuration, assumed) 5.6 g. Compound 1 was furtherseparated by SFC with the following conditions: Column: Phenomenex Lux 5u Cellulose-3, 5×25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH;Flow rate: 150 mL/min; Gradient: 40% B; Detector: UV 220/254 nm; RT11:4.84 min; RT12: 6.2 min; The compound 2 was further separated by SFCwith the following conditions: Column: Phenomenex Lux 5 u Cellulose-3,5×25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH; Flow rate:200mL/min; Gradient: 50% B; Detector: UV 220/254 nm; RT21: 2.98 min; RT22:4.58 min.

The two first peak fractions (RT11: 4.84 min and RT21: 2.98 min) weremixed and concentrated in vacuum to give the title cis-intermediateG-3-52 as an off-white solid (6 g, 44%): ¹H NMR (400 MHz, CDCl₃) δ 8.32(s, 1H), 6.87 (dd, J=8.0, 1.5 Hz, 1H), 6.83 (d, J=1.5 Hz, 1H), 6.73 (d,J=8.0 Hz, 1H), 5.24 (dd, J=12.6, 5.3 Hz, 1H), 3.45 (s, 3H), 3.01-2.95(m, 1H), 2.88-2.68 (m, 2H), 2.63 (d, J=7.5 Hz, 2H), 2.28-2.23 (m, 3H),2.03-2.01 (m, 1H), 1.81-1.68 (m, 1H), 1.50-1.45 (m, 15H), 1.40-1.26 (m,2H); LC/MS (ESI, m/z): [(M+1−56)]⁺=414.15.

The two second peak fractions (RT12: 6.2 min and RT22: 4.58 min) weremixed and concentrated in vacuum to give the title trans-intermediateG-3-53 as an off-white solid. (2 g, 14%): ¹H NMR (400 MHz, CDCl₃) δ N—H(not shown), 6.86 (dd, J=8.0, 1.5 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 6.72(d, J=8.0 Hz, 1H), 5.27 (dd, J=12.6, 5.3 Hz, 1H), 3.45 (s, 3H),2.98-2.87 (m, 2H), 2.82-2.62 (m, 1H), 2.54 (d, J=7.1 Hz, 2H), 2.26-2.23(m, 1H), 2.08-2.05 (m, 2H), 1.76-1.72 (m, 4H), 1.56-1.38 (m, 11H),1.02-0.95 (m, 4H); LC/MS (ESI, m/z): [(M+1−56)]⁺=414.15.

Benzyl4-[1-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]azetidin-3-yl]butanoate(Intermediate G-3-54)

Step 1. 1,5-Di-tert-butyl 2-[(4-bromo-2-nitrophenyl)amino]pentanedioate.A solution of 4-bromo-1-fluoro-2-nitrobenzene (498.9 g, 2.26 mol),1,5-di-tert-butyl (25)-2-aminopentanedioate hydrochloride (806.74 g,2.73 mol) and Na₂CO₃ (963.54 g, 9.09 mol) in THF (3.00 L)/H₂O (3.00 L)was stirred for 24 h at 60° C. under nitrogen atmosphere. The resultingsolution was cooled down to room temperature and was diluted with water(2 L). The mixture was extracted with petroleum ether (2×3 L). Thecombined organic phase was acidified to pH 5 with aqueous HCl (0.5 M, 2L). The combined organic phase was washed with water (2×3 L), brine (2L), dried with Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure to afford the title compound as a yellow oil (1000 g,96%): ¹H NMR (400 MHz, DMSO-d₄) δ 8.27 (d, J=7.6 Hz, 1H), 8.20 (d, J=2.4Hz, 1H), 7.70 (dd, J=9.2, 2.4 Hz, 1H), 7.03 (d, J=9.3 Hz, 1H), 4.55-4.46(m, 1H), 2.40-2.28 (m, 2H), 2.17-1.99 (m, 2H), 1.44 (s, 9H), 1.35 (s,9H); LC/MS (ESI, m/z): [(M+1)]⁺=459.05, 461.05.

Step 2. 1,5-Di-tert-butyl 2-[(2-amino-4-bromophenyl)amino]pentanedioate.The title compound was prepared according to the procedure of step 5 toprepare Intermediate A. ¹H NMR (400 MHz, DMSO-d₆) δ 6.69 (d, J=2.4 Hz,1H), 6.65-6.52 (m, 1H), 6.18 (d, J=8.4 Hz, 1H), 4.98 (s, 2H), 4.76 (d,J=9.2 Hz, 1H), 3.82-3.76 (m, 1H), 2.40 (t, J=7.4 Hz, 2H), 1.99-1.85 (m,2H), 1.40 (d, J=6.2 Hz, 18H); LC/MS (ESI, m/z): [(M+1)]⁺=429.20, 431.20.

Step 3. 1,5-Di-tert-butyl2-(5-bromo-2-oxo-3H-1,3-benzodiazol-1-yl)pentanedioate. A solution of1,5-di-tert-butyl 2-[(2-amino-4-bromophenyl)amino]pentanedioate (950.00g, 2.21 mol) and CDI (717.55 g, 4.43 mol) in dioxane (12.00 L) wasstirred for overnight at 90° C. under nitrogen atmosphere. The mixturewas allowed to cool down to room temperature. The resulting mixture wasconcentrated under reduced pressure. The residue was purified bytrituration with water (10 L)/petroleum ether (10 L). The resultingmixture was filtered. The filter cake was washed with water (2×5 L) anddried under reduced pressure to afford the title compound as a lightpink solid (760 g, 75%): ¹H NMR (400 MHz, CD₃OD) δ 7.27-7.18 (m, 2H),7.08 (d, J=1.0 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 5.04 (dd, J=10.7, 5.1Hz, 1H), 2.56-2.32 (m, 2H), 2.24 (dd, J=7.6, 6.4 Hz, 2H), 1.40 (d,J=11.9 Hz, 18H); LC/MS (ESI, m/z): [(M+1)]⁺=455.05, 457.05.

Step 4. 1,5-Di-tert-butyl(2-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)pentanedioate. To astirred solution of 1,5-di-tert-butyl2-(5-bromo-2-oxo-3H-1,3-benzodiazol-1-yl)pentanedioate (760.00 g, 1.67mol) and K₂CO₃ (922.69 g, 6.68 mol) in DMF (3.50 L) was added CH₃I(592.26 g, 4.17 mol) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for overnight at room temperature undernitrogen atmosphere. The resulting solution was diluted with water (30L) and triturated for 2 h. After filtration, the filter cake wastriturated with petroleum ether (10 L) for 2 h again. The resultingmixture was filtered. The filter cake was washed with petroleum ether (1L) and dried under reduced pressure to afford the title compound as awhite solid (675 g, 86%): ¹H NMR (400 MHz, CD₃OD) δ 7.39 (d, J=1.8 Hz,1H), 7.26 (dd, J=8.4, 1.9 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.07 (dd,J=10.7, 5.1 Hz, 1H), 3.43 (s, 3H), 2.56-2.34 (m, 2H), 2.23 (dd, J=7.6,6.4 Hz, 2H), 1.40 (d, J=14.9 Hz, 18H); LC/MS (ESI, m/z):[(M+1)]⁺=469.30, 471.30.

Step 5. 1,5-Dibutyl2-(5-[3-[4-(benzyloxy)-4-oxobutyl]azetidin-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)pentanedioate.The title compound was prepared according to the procedure to prepareIntermediate G-3-39. ¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.23 (m, 5H), 6.85(d, J=8.4 Hz, 1H), 6.26 (d, J=2.1 Hz, 1H), 6.08 (dd, J=8.4, 2.2 Hz, 1H),5.10 (s, 2H), 4.91 (dd, J=10.3, 5.1 Hz, 1H), 3.89 (t, J=7.3 Hz, 2H),3.36-3.34 (m, 3H), 3.27 (s, 3H), 2.72-2.59 (m, 1H), 2.46-2.36 (m, 2H),2.36-2.19 (m, 2H), 2.19-2.03 (m, 2H), 1.56 (q, J=7.2, 5.3 Hz, 3H), 1.34(d, J=7.6 Hz, 18H); LC/MS (ESI, m/z): [(M+1)]⁺=622.50.

The intermediates in Table 34 were prepared according to step 5 of theprocedure to prepare Intermediate G-3-54.

TABLE 34 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-5-1

1,5-dibutyl 2-(5- [4-[4- (benzyloxy)-4- oxobutyl]piperidin-1-yl]-3-methyl- 2-oxo-1,3- benzodiazol-1- yl)pentanedioate 650.50 (400MHz, DMSO-d₆) δ 7.41-7.29 (m, 5H), 6.88 (d, J = 8.6 Hz, 1H), 6.80 (d, J= 2.2 Hz, 1H), 6.62 (dd, J = 8.6, 2.3 Hz, 1H), 5.09 (d, J = 4.2 Hz, 2H),4.92 (dd, J = 10.3, 5.1 Hz, 1H), 3.57 (d, J = 11.8 Hz, 2H), 3.29 (s,3H), 2.58 (t, J = 11.6 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.32- 2.20 (m,2H), 2.20-2.06 (m, 2H), 1.73 (d, J = 12.2 Hz, 2H), 1.64-1.57 (m, 3H),1.34 (d, J = 10.5 Hz, 18H), 1.28-1.21 (m, 4H)

Step 6.2-(5-[3-[4-(Benzyloxy)-4-oxobutyl]azetidin-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)pentanedioicacid. A mixture of 1,5-dibutyl2-(5-[3-[4-(benzyloxy)-4-oxobutyl]azetidin-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)pentanedioate(1.80 g, 2.895 mmol) in TFA (25.00 mL) was stirred for 1 h at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure to give the crude title compound(2.6 g), which was used in the next step directly without furtherpurification: LC/MS (ESI, m/z): [(M+1)]⁺=510.20.

The intermediates in Table 35 were prepared according to step 6 of theprocedure to prepare Intermediate G-3-54.

TABLE 35 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-6-1

2-(5-[4-[4- (benzyloxy)-4- oxobutyl]piperidin- 1-yl]-3-methyl-2-oxo-1,3- benzodiazol-1- yl)pentanedioic acid 538.20 Used in the nextstep without further purification

Step 7. Benzyl4-[1-[1-(2,6-dioxooxan-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]azetidin-3-yl]butanoate.A mixture of2-(5-[3-[4-(benzyloxy)-4-oxobutyl]azetidin-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)pentanedioicacid (2.60 g, 5.102 mmol) and Ac₂O (7.00 mL) in pyridine (20.00 mL) wasstirred for 1 h at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure to give thecrude title compound (4.7 g), which was used in the next step directlywithout further purification: LC/MS (ESI, m/z): [(M+1)]⁺=492.35.

The intermediates in Table 36 were prepared according to step 7 of theprocedure to prepare Intermediate G-3-54.

TABLE 36 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-7-1

benzyl 4-[1-[1- (2,6-dioxooxan- 3-yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]piperidin-4- yl]butanoate 520.20 Used in the next stepwithout further purification

Step 8.2-(5-[3-[4-(Benzyloxy)-4-oxobutyl]azetidin-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)-4-carbamoylbutanoicacid. NH₃ (g) was bubbled in a stirred mixture of benzyl4-[1-[1-(2,6-dioxooxan-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]azetidin-3-yl]butanoate(4.50 g, 9.155 mmol) in THF (30.00 mL) at room temperature for 30 min.The resulting mixture was stirred for 2 h at room temperature undernitrogen atmosphere. The resulting mixture was concentrated underreduced pressure. The residue was purified by reverse phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 330 g; Eluent A: water (plus 10 mmol/L TFA); Eluent B: ACN;Gradient: 15%-45% B in 25 min; Flow rate: 80 mL/min; Detector: UV220/254 nm; desired fractions were collected at 35% B and concentratedunder reduced pressure to afford the title compound as a yellow solid(1.5 g, 32%): ¹H NMR (400 MHz, DMSO-d₄) δ 7.38-7.32 (m, 6H), 7.23-7.20(m, 1H), 6.95 (d, J=16.0 Hz, 1H), 6.73 (s, 1H), 6.56 (s, 1H), 6.34-6.32(m, 1H), 5.10 (s, 3H), 4.95 (dd, J=10.8, 4.8 Hz, 1H), 4.06 (t, J=7.4 Hz,2H), 3.64-3.54 (m, 3H), 2.77-2.68 (m, 1H), 2.40 (t, J=7.0 Hz, 3H),2.06-1.95 (m, 1H), 1.94-1.86 (m, 1H), 1.65-1.52 (m, 6H); LC/MS (ESI,m/z): [(M+1)]⁺=509.40.

The intermediates in Table 37 were prepared according to step 8 of theprocedure to prepare Intermediate G-3-54.

TABLE 37 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H NMR G-8-1

2-(5-[4-[4- (benzyloxy)-4- oxobutyl]piperidin- 1-yl]-3-methyl-2-oxo-1,3- benzodiazol-1- yl)-4- carbamoylbutanoic acid 537.45 ¹H NMR(400 MHz, DMSO-d₆) δ 7.70-7.43 (m, 1H), 7.46-7.30 (m, 5H), 7.21 (s, 2H),6.74 (s, 1H), 5.11 (s, 2H), 5.05 (dd, J = 10.8, 4.9 Hz, 1H), 3.61-3.58(m, 4H), 3.37 (s, 3H), 2.41 (t, J = 7.3 Hz, 3H), 2.36-2.22 (m, 1H),2.08-1.98 (m, 2H), 1.98-1.85 (m, 3H), 1.70- 1.41 (m, 6H), 1.35-1.29 (m,2H)

Step 9. Benzyl4-[1-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]azetidin-3-yl]butanoate.The title compound was prepared according to the procedure of step 3 toprepare Intermediate G-3-54. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),7.47-7.25 (m, 5H), 6.98 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 6.30 (d, J=8.5Hz, 1H), 5.31 (dd, J=12.8, 5.3 Hz, 1H), 5.10 (s, 2H), 4.04 (t, J=7.6 Hz,2H), 3.55 (d, J=6.9 Hz, 2H), 3.31 (s, 3H), 2.92-2.86 (m, 1H), 2.80-2.57(m, 3H), 2.40 (t, J=6.9 Hz, 2H), 2.06-1.91 (m, 1H), 1.70-1.43 (m, 4H);LC/MS (ESI, m/z): [(M+1)]⁺=491.15.

The intermediates in Table 38 were prepared according to step 9 of theprocedure to prepare Intermediate G-3-54.

TABLE 38 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-3-55

benzyl 4-[1-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]piperidin-4- yl]butanoate 519.20 (400 MHz, DMSO-d₆) δ11.14 (s, 1H), 7.52 (s, 1H), 7.43-7.30 (m, 5H), 7.24 (s, 2H), 5.41 (dd,J = 12.7, 5.4 Hz, 1H), 5.11 (s, 2H), 3.66-3.52 (m, 3H), 3.38 (s, 3H),2.95-2.87 (m, 1H), 2.81-2.57 (m, 2H), 2.41 (t, J = 7.3 Hz, 2H),2.06-1.98 (m, 1H), 1.97-1.90 (m, 2H), 1.75- 1.40 (m, 6H), 1.34-1.29 (m,2H)

Step 4.2-[2-(2-[3-[1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]ethoxy)ethoxy]aceticacid. A solution of tert-butyl2-[2-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]ethoxy)ethoxy]acetate(700 mg, 1.35 mmol) in DCM (10.0 mL) and TFA (10.0 mL) was stirred for30 min at room temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by reversed phase flash chromatography with the followingconditions: Column: WelFlash™ C18-I, 20-40 um, 330 g; Eluent A: water(plus 10 mmol/L FA); Eluent B: ACN; Gradient: 20%-40% B in 20 min; Flowrate: 80 mL/min; Detector: UV 220/254 nm; desired fractions werecollected at 31% B and concentrated under reduced pressure to afford thetitle compound as a light yellow solid (520 mg, 83%): ¹H NMR (400 MHz,DMSO-d₆) δ 12.58 (s, 1H), 11.09 (s, 1H), 7.09-6.97 (m, 2H), 6.88 (dd,J=8.1, 1.6 Hz, 1H), 5.34 (dd, J=12.7, 5.4 Hz, 1H), 4.03 (s, 2H),3.62-3.48 (m, 8H), 3.40 (t, J=6.5 Hz, 2H), 3.33 (s, 3H), 2.97-2.85 (m,1H), 2.77-2.58 (m, 4H), 2.06-1.96 (m, 1H), 1.88-1.77 (m, 2H); MS (ESI,m/z): [(M+1)]⁺=464.30.

The following intermediates in Table 39 were prepared according Step 4of the procedure to prepare Intermediate G.

TABLE 39 Characterization data for intermediates prepared according toprocedure above. MS: Intermediate Structure Chemical Name [(M + 1)]⁺¹H-NMR G-4-1 

3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 2,3-dihydro-1H-1,3-benzodiazol-5- yl]propanoic acid 332.2  (400 MHz, DMSO-d₆) δ 12.13 (s,1H), 11.10 (s, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H),6.91 (dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 3.32(s, 3H), 2.97-2.78 (m, 3H), 2.78-2.53 (m, 4H), 2.00 (s, 1H). G-4-2 

15-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 2,3-dihydro-1H-1,3-benzodiazol-5-yl]- 3,6,9,12- tetraoxapentadecanoic acid 508.3  (400 MHz,DMSO-d₆) 12.58 (s, 1H), 11.09 (s, 1H), 7.08-6.97 (m, 2H), 6.88 (dd, J =8.0, 1.6 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.02 (d, J = 2.0 Hz,2H), 3.58 (dd, J = 6.4, 3.5 Hz, 2H), 3.54 (s, 5H), 3.51-3.44 (m, 3H),3.43- 3.35 (m, 4H), 2.90 (ddd, J = 17.3, 13.0, 5.2 Hz, 1H), 2.77-2.59(m, 4H), 2.08 (s, 3H), 2.00 (dd, J = 11.1, 5.4 Hz, 1H), 1.88-1.76 (m,2H). G-4-3 

[2-(2-[3-[3-methyl- 1-(1-methyl-2,6- dioxopiperidin-3- yl)-2-oxo-1,3-benzodiazol-5- yl]propoxy]ethoxy) ethoxy]acetic acid 578.3  (400 MHz,DMSO-d₆) δ 12.57 (s, 1H), 7.08-6.96 (m, 2H), 6.86 (t, J = 7.8 Hz, 1H),5.40 (dt, J = 12.8, 6.2 Hz, 1H), 4.02 (d, J = 6.4 Hz, 2H), 3.62-3.49 (m,5H), 3.49 (t, J = 3.7 Hz, 2H), 3.43-3.35 (m, 2H), 3.03 (d, J = 6.9 Hz,3H), 2.82- 2.60 (m, 4H), 2.49 (s, 2H), 2.10-1.96 (m, 2H), 1.81 (q, J =7.3 Hz, 3H). G-4-4 

2-(2-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propoxy]ethoxy) acetic acid 420.3 (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 11.09 (s, 1H), 7.04 (d, J = 13.4 Hz,2H), 6.88 (d, J = 8.2 Hz, 1H), 5.34 (dd, J = 12.8, 5.4 Hz, 1H), 4.05 (s,2H), 3.61 (dd, J = 5.9, 3.5 Hz, 2H), 3.51 (dd, J = 5.9, 3.6 Hz, 2H),3.40 (t, J = 6.4 Hz, 2H), 3.33 (s, 3H), 2.88 (d, J = 17.8 Hz, 1H),2.77-2.58 (m, 4H), 2.05-1.97 (m, 1H), 1.81 (q, J = 7.4, 7.0 Hz, 2H).G-4-5 

(2-[3-[3-methyl-1- (1-methyl-2,6- dioxopipendin-3- yl)-2-oxo-1,3-benzodiazol-5- yl]propoxy]ethoxy) acetic acid 432.2  (400 MHz, DMSO-d₆)δ 7.08-6.98 (m, 2H), 6.87 (d, J = 8.1 Hz, 1H), 5.41 (dd, J = 13.2, 5.3Hz, 1H), 4.04 (s, 2H), 3.61 (dd, J = 5.9, 3.7 Hz, 2H), 3.52 (dd, J =5.9, 3.6 Hz, 2H), 3.41 (t, J = 6.4 Hz, 2H), 3.33 (s, 2H), 3.04 (s, 3H),3.02-2.91 (m, 1H), 2.82-2.62 (m, 4H), 2.02 (d, J = 12.0 Hz, 1H), 1.82(p, J = 6.7 Hz, 3H). G-4-6 

2-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 2,3-dihydro- 1H-1,3-benzodiazol-5- yl]propoxy]acetic acid 376.1  (400 MHz, DMSO-d₆) δ 12.59(s, 1H), 11.10 (s, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.01 (d, J = 8.0 Hz,1H), 6.89 (dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H),4.01 (s, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.33 (s, 3H), 2.90 (ddd, J =17.1, 13.1, 5.3 Hz, 1H), 2.77-2.58 (m, 4H), 2.06-1.96 (m, 1H), 1.83 (dq,J = 8.7, 6.6 Hz, 2H) G-4-34 

3-(2-[2-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]ethyl]phenyl) propanoic acid 436.10 (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 7.26-7.23 (m, 1H), 7.20-7.17 (m, 1H),7.18-7.09 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (dd, J = 8.1, 1.6 Hz,1H), 5.35 (dd, J = 12.6, 5.4 Hz, 1H), 3.34 (s, 3H), 2.94-2.83 (m, 9H),2.78-2.58 (m, 2H), 2.04-1.96 (m, 1H) G-4-35 

[(1r,4r)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetic acid 428.15 (400 MHz,DMSO-d₆) δ 11.91 (s, 1H), 11.08 (s, 1H), 6.99 (d, J = 8.1 Hz, 2H), 6.81(dd, J = 8.0, 1.6 Hz, 1H), 5.36 (dd, J = 12.7, 5.4 Hz, 1H), 2.96-2.85(m, 1H), 2.77-2.58 (m, 3H), 2.48 (s, 2H), 2.21-2.17 (m, 2H), 2.08-1.97(m, 1H), 1.70-1.64 (m, 5H), 1.42-1.36 (m, 2H), 1.22-1.10 (m, 2H),0.98-0.78 (m, 5H) G-4-36 

(4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]methyl]piperazin- 1-yl)acetic acid 416.12 Used in the next stepwithout further purification G-4-37 

(4-[[1-(2,6- Dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]methyl]piperidin- 1-yl)acetic acid 415.10 (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 9.75-9.58 (s, 1H), 7.12-6.99 (m, 2H), 6.87 (dd, J = 8.1, 1.5Hz, 1H), 5.35 (dd, J = 12.8, 5.3 Hz, 1H), 4.13-4.05 (m, 2H), 3.49 (d, J= 11.9 Hz, 2H), 3.33 (s, 3H), 3.02-2.84 (m, 2H), 2.77-2.55 (m, 4H),1.96-1.89 (m, 1H), 1.78 (d, J = 13.1 Hz, 3H), 1.58-1.44 (m, 3H) G-4-38 

4-[4-[1-(2,6- Dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]piperidin-1- yl]butanoic acid 429.20 (400 MHz, DMSO-d₆) δ 11.09 (s,1H), 7.12-7.00 (m, 2H), 6.92 (dd, J = 8.2, 1.6 Hz, 1H), 5.35 (dd, J =12.8, 5.3 Hz, 1H), 3.81-3.78 (m, 1H), 3.35 (s, 3H), 2.97-2.85 (m, 1H),2.84-2.66 (m, 4H), 2.66-2.56 (m, 3H), 2.33 (t, J = 7.0 Hz, 2H),2.06-1.70 (m, 8H) G-4-39 

3-[4-[1-(2,6- Dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]piperidin-1- yl]propanoic acid 415.15 (400 MHz, DMSO-d₆) δ 11.09 (s,1H), 7.10 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.92 (dd, J =8.2, 1.6 Hz, 1H), 5.35 (dd, J = 12.7, 5.3 Hz, 1H), 3.34 (s, 3H), 3.16(d, J = 11.7 Hz, 2H), 3.00-2.56 (m, 5H), 2.47 (d, J = 7.2 Hz, 2H),2.40-2.29 (m, 2H), 2.08-1.95 (m, 1H), 1.89-1.67 (m, 5H) G-4-40 

[(1s,4s)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetic acid 414.15 (300 MHz,DMSO-d₆) δ 12.50 (br, 1H), 11.06 (s, 1H), 6.70-6.96 (m, 2H), 6.82 (dd, J= 8.1, 1.5 Hz, 1H), 5.32 (dd, J = 12.7, 5.4 Hz, 1H), 3.31 (s, 3H),3.00-2.79 (m, 1H), 2.78-2.53 (m, 4H), 2.21 (d, J = 7.3 Hz, 2H),2.04-2.00 (m, 1H), 1.91-1.86 (m, 1H), 1.70-1.67 (m, 1H), 1.55-1.48 (m, 6H) 1.35-1.28 (m, 2H). G-4-41 

[(1r,4r)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetic acid 414.15 (400 MHz,DMSO-d₆) δ 11.96 (s, 1H), 11.09 (s, 1H), 7.02-6.96 (m, 2H), 6.83- 6.81(m, 1H), 5.36-5.32 (m, 1H), 3.32 (s, 4H), 2.96-2.85 (m, 1H), 2.77-2.58(m, 2H), 2.48 (s, 2H), 2.09-2.05 (m, 3H), 2.04-1.97 (m, 1H), 1.67 (t, J= 13.2 Hz, 4H), 1.01-0.85 (m, 4H) G-4-42 

6-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]amino]hexanoic acid 389.20 (400 MHz, CD₃OD) δ 7.39 (d, J = 2.0 Hz,1H), 7.31 (d, J = 8.5 Hz, 1H), 7.28- 7.19 (m, 1H), 5.41 (dd, J = 12.5,5.4 Hz, 1H), 3.47-3.45 (m, 4H), 3.50-3.41 (m, 1H), 3.02-2.75 (m, 3H),2.35-2.32 (m, 2H), 2.23-2.19 (m, 1H), 1.85-1.77 (m, 1H), 1.77 (t, J =6.4 Hz, 1H), 1.67 (p, J = 7.3 Hz, 2H), 1.51-1.47 (m, 2H). G-4-85 

5-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]cyclobutyl] pentanoic acid 414.20 (300 MHz, Chloroform-d) δ 8.74 (s,1H), 7.06-6.94 (m, 2H), 6.89-6.73 (m, 1H), 5.51-5.36 (m, 1H), 3.69-3.62(m, 1H), 3.52 (s, 3H), 3.48-3.31 (m, 1H), 3.07-2.84 (m, 2H), 2.81-2.68(m, 1H), 2.61-2.36 (m, 2H), 2.34-2.25 (m, 3H), 2.18-2.12 (m, 1H),1.83-1.52 (m, 4H), 1.52-1.15 (m, 4H) G-4-86 

4-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]cyclobutyl]butanoic acid 400.10 (400 MHz, Methanol-d₄) δ 7.14-6.93(m, 3H), 5.32 (ddd, J = 12.3, 5.5, 2.3 Hz, 1H), 3.67 (p, J = 7.6, 6.8Hz, 1H), 3.51-3.39 (m, 3H), 2.97-2.93 (m, 1H), 2.82-2.78 (m, 2H),2.56-2.53 (m, 1H), 2.34-2.30 (m, 4H), 2.19-2.15 (m, 2H), 1.80-1.43 (m,5H), 1.43-1.12 (m, 1H). G-4-109

[(1s,4s)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetic acid 414.15 (400 MHz,DMSO-d₆) δ 11.81 (s, 1H), 11.09 (s, 1H), 7.01-6.99 (m, 2H), 6.83 (dd, J= 8.0, 1.5 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 3.32 (s, 3H), 2.97-2.83 (m, 1H), 2.77-2.62 (m, 2H), 2.59 (d, J = 6.3 Hz, 2H), 2.22 (d, J =7.3 Hz, 2H), 2.04-1.98 (m, 1H), 1.93-1.87 (m, 1H), 1.78-1.64 (m, 1H),1.48-1.38 (m, 6H), 1.33-1.26 (m, 2H) G-4-110

[(1s,4s)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetic acid 414.15 (400 MHz,DMSO-d₆) δ 11.81 (s, 1H), 11.09 (s, 1H), 7.01-6.99 (m, 2H), 6.83 (dd, J= 8.0, 1.5 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 3.32 (s, 3H), 2.97-2.83 (m, 1H), 2.77-2.62 (m, 2H), 2.59 (d, J = 6.3 Hz, 2H), 2.22 (d, J =7.3 Hz, 2H), 2.04-1.98 (m, 1H), 1.93-1.87 (m, 1H), 1.78-1.64 (m, 1H),1.48-1.38 (m, 6H), 1.33-1.26 (m, 2H) G-4-111

3-[(1s,4s)-4-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]cyclohexyl] propanoic acid 414.15 (300 MHz,DMSO-d₆) δ 11.08 (s, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 8.1 Hz,1H), 6.90 (dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H),3.34 (s, 3H), 2.99-2.83 (m, 1H), 2.81-2.57 (m, 2H), 2.27 J = 7.6 Hz,2H), 2.01 (d, J = 11.6 Hz, 1H), 1.83-1.80 (m, 4H), 1.48-1.44 (m, 4H),1.32-1.29 (m, 1H), 1.16-0.97 (m, 2H) G-4-112

3-[(1r,4r)-4-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]cyclohexyl] propanoic acid 414.15 (300 MHz,DMSO-d₆) δ 12.00 (s, 1H), 11.08 (s, 1H), 7.10 (d, J = 1.5 Hz, 1H), 7.01(d, J = 8.1 Hz, 1H), 6.92 (dd, J = 8.1, 1.5 Hz, 1H), 5.34 (dd, J = 12.7,5.4 Hz, 1H), 3.33-3.31 (m, 4H), 2.99- 2.81 (m, 1H), 2.69-2.61 (m, 2H),2.25- 2.21 (m, 2H), 2.07-1.95 (m, 1H), 1.65- 1.61 (m, 11H)

[4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]aceticacid. (Intermediate G-4-7)

A solution of tert-butyl2-[4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl] acetate (270 mg, 0.60 mmol) in DCM (3.00 mL) wastreated with TFA (3.00 mL) for 20 min at 25° C. under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure. The residue was dissolved in DMSO (5.00 mL) and TEA (1.00 mL).To the solution was added Boc₂O (196 mg, 0.90 mmol) at 25° C. undernitrogen atmosphere. The resulting mixture was stirred for 30 min at 25°C. under nitrogen atmosphere. The resulting mixture was purified byreversed phase flash chromatography with the following conditions:Column: WelFlash™ C18-I, 20-40 um, 330 g; Eluent A: water (plus 10mmol/L AcOH); Eluent B: ACN; Gradient: 30%-50% B in 20 min; Flow rate:80 mL/min; Detector: UV 220/254 nm; desired fractions were collected at45% B and concentrated under reduced pressure to afford the titlecompound as a light yellow oil (150 mg, 63): ¹H NMR (400 MHz, DMSO-d₆) δ12.26 (s, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.22-7.20 (m, 3H), 6.67 (s, 1H),6.61 (d, J=9.1 Hz, 1H), 4.51-4.40 (m, 2H), 3.55 (s, 2H), 3.49-3.38 (m,2H), 2.14-1.95 (m, 2H, 1.79 (dddd, J=13.4, 9.8, 6.1, 3.0 Hz, 1H), 1.50(td, J=9.3, 8.9, 5.0 Hz, 1H), 1.39 (s, 9H), 1.06 (d, J=6.0 Hz, 3H); MS(ESI, m/z): [(M+1)]⁺=395.30.

The following intermediates in Table 40 were prepared according to theabove procedure for Intermediate G-4-7.

TABLE 40 Characterization data for intermediates prepared according toprocedure above. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺¹H-NMR G-4-8 

3-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2-yl]oxy]methyl) phenyl]propanoic acid 409.2 (400 MHz, CDCl₃) δ 7.26 (d, J= 7.8 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 6.62 (s, 1H), 6.36 (s, 1H),4.89 (d, J = 9.6 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.37 (d, J = 11.6Hz, 1H), 3.68-3.53 (m, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.66 (t, J = 7.7Hz, 2H), 2.27 (td, J = 8.0, 4.7 Hz, 2H), 1.97-1.88 (m, 1H), 1.74- 1.59(m, 1H), 1.45 (s, 9H), 1.20 (d, J = 6.3 Hz, 3H). G-4-9 

[3-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]propoxy]acetic acid 453.3 (400 MHz, DMSO-d₆) δ12.45 (s, 1H), 7.23 (dd, J = 7.9, 5.6 Hz, 3H), 7.16 (dd, J = 8.0, 5.9Hz, 2H), 6.72-6.55 (m, 2H), 4.50-4.37 (m, 2H), 3.98 (s, 2H), 3.52-3.36(m, 4H), 2.62 (td, J = 8.0, 5.6 Hz, 2H), 2.09-2.07 (m, 3H), 1.91 (d, J =5.7 Hz, 1H), 1.83-1.77 (m, 2H), 1.39 (s, 9H), 1.06 (t, J = 5.5 Hz, 3H).G-4-10

[3-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]propoxy]acetic acid 467.2 (400 MHz, DMSO-d₆) δ12.48 (s, 1H), 7.34-7.08 (m, 5H), 6.69-6.59 (m, 2H), 4.43 (t, J = 4.4Hz, 2H), 3.94 (d, J = 5.1 Hz, 2H), 3.49-3.35 (m, 4H), 2.57 (q, J = 6.0,3.5 Hz, 2H), 2.13-1.96 (m, 3H), 1.84-1.72 (m, 1H), 1.60 (s, 2H), 1.52(d, J = 8.7 Hz, 2H), 1.46- 1.32 (m, 9H), 1.06 (d, J = 6.0, 3H). G-4-11

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]pentanoic acid 437.3 (400 MHz, DMSO-d₆) δ 11.96(s, 1H), 7.27-7.17 (m, 3H), 7.14 (d, J = 7.9 Hz, 2H), 6.67 (s, 1H), 6.59(d, J = 9.0 Hz, 1H), 4.51- 4.37 (m, 2H), 3.41 (h, J = 7.4, 6.0 Hz, 2H),2.56 (t, J = 7.2 Hz, 2H), 2.22 (t, J = 7.1 Hz, 2H), 2.13-1.95 (m, 2H),1.85-1.73 (m, 1H), 1.68-1.35 (m, 5H), 1.39 (s, 9H), 1.06 (d, J = 6.0 Hz,3H). G-4-12

(2-[3-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]propoxy]ethoxy) acetic acid497.3 (400 MHz, DMSO-d₆) δ 7.23 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.7Hz, 2H), 6.73- 6.57 (m, 2H), 4.50-4.37 (m, 2H), 4.03 (s, 2H), 3.60 (dd,J = 5.9, 3.7 Hz, 2H), 3.50 (dd, J = 5.9, 3.6 Hz, 2H), 3.39-3.37 (m, 5H),2.60 (t, J = 7.7 Hz, 2H), 2.07-1.96 (m, 2H), 1.84-1.73 (m, 3H), 1.39 (s,9H), 1.06 (d, J = 6.0 Hz, 3H). G-4-13

[2-(2-[3-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]propoxy]ethoxy) ethoxy]aceticacid 541.4 (400 MHz, CDCl₃) δ 7.26 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 7.8Hz, 2H), 6.52 (s, 1H), 6.26 (s, 1H), 4.86 (d, J = 9.7 Hz, 1H), 4.61 (d,J = 11.6 Hz, 1H), 4.38 (d, J = 11.5 Hz, 1H), 4.19 (s, 2H), 3.79 (dd, J =6.3, 3.1 Hz, 2H), 3.76-3.66 (m, 5H), 3.63-3.54 (m, 3H), 3.48 (t, J = 6.4Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.28 (t, J = 6.9 Hz, 2H), 1.92 (p, J= 6.9 Hz, 2H), 1.76-1.64 (m, 1H), 1.45 (s, 9H), 1.21 (d, J = 6.3 Hz,3H). G-4-14

15-[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]-3,6,9,12- tetraoxapentadecanoic acid 585.4(400 MHz, DMSO-d₆) δ 12.55 (s, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.15 (d, J= 7.8 Hz, 2H), 6.67 (s, 1H), 6.60 (d, J = 9.1 Hz, 1H), 4.49-4.38 (m,2H), 4.01 (s, 2H), 3.62- 3.44 (m, 12H), 3.41-3.36 (m, 3H), 2.60 (t, J =7.6 Hz, 2H), 2.10-1.96 (m, 3H), 1.82- 1.75 (m, 3H), 1.48 (s, 1H), 1.39(s, 9H), 1.06 (d, J = 6.0 Hz, 3H). G-4-15

4-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]butanoic acid 423.2 (400 MHz, CDCl₃) δ 7.26-7.12(m, 4H), 6.50 (s, 1H), 5.72 (s, 1H), 4.88 (d, J = 9.5 Hz, 1H), 4.71-4.50(m, 1H), 4.38 (d, J = 11.4 Hz, 1H), 3.71-3.55 (m, 2H), 3.51 (s, 3H),2.74-2.62 (m, 3H), 2.39-2.25 (m, 5H), 2.10-1.96 (, 3H), 1.46 (d, J = 6.0Hz, 9H). G-4-16

[2-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]ethoxy]acetic acid 439.4 (400 MHz, DMSO-d₆) δ12.55 (s, 1H), 7.33-7.12 (m, 4H), 6.68 (s, 1H), 6.61 (d, J = 9.1 Hz,1H), 4.49-4.38 (m, 2H), 4.00 (s, 2H), 3.66 (d, J = 14.0 Hz, 1H),3.48-3.36 (m, 3H), 2.82 (t, J = 7.0 Hz, 2H), 2.21-1.89 (m, 3H), 1.39 (s,9H), 1.06 (d, J = 5.9 Hz, 3H). G-4-17

(2-[2-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]- 5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]ethoxy]ethoxy) acetic acid483.4 (400 MHz, DMSO-d₆) δ 7.30-7.13 (m, 4H), 6.75-6.53 (m, 2H),4.52-4.35 (m, 2H), 4.01 (s, 2H), 3.63-3.49 (m, 6H), 3.48-3.34 (m, 2H),2.80 (t, J = 7.1 Hz, 2H), 2.03 (dd, J = 12.8, 7.0 Hz, 2H), 1.78 (d, J =9.0 Hz, 1H), 1.56-1.43 (m, 1H), 1.39 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H).G-4-18

[2-(2-[2-[4- ([[(2R,3S)-3-[(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]ethoxy]ethoxy) ethoxy]aceticacid 527.3 (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 7.25-7.20 (m, 4H),6.66-6.61 (m, 2H), 4.42 (s, 1H), 4.19-3.88 (m, 2H), 3.79-3.47 (m, 8H),2.84 (s, 2H), 2.81-2.78 (m, 4H), 2.06 (s, 3H), 1.79 (s, 2H), 1.42 (s,6H), 1.38 (s, 3H), 1.06 (s, 3H). G-4-19

14-[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]-3,6,9,12- tetraoxatetradecanoic acid 571.4(400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 7.30- 7.15 (m, 4H), 6.73-6.55 (m,2H), 4.50-4.39 (m, 2H), 4.02 (s, 2H), 3.65-3.53 (m, 4H), 3.53 (dd, J =5.8, 3.2 Hz, 10H), 3.47-3.36 (m, 2H), 2.79 (t, J = 7.0 Hz, 2H),2.12-1.99 (m, 2H), 1.79 (dt, J = 6.7, 3.6 Hz, 1H), 1.55-1.43 (m, 1H),1.39 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H). G-4-28

3-[6-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) naphthalen-2- yl]propanoic acid 459.2 (400 MHz, CD₃OD) δ7.79 (m, 3H), 7.67 (d, J = 17.6 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.38(d, J = 7.8 Hz, 1H), 4.75 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.8 Hz,1H), 3.65- 3.54 (m, 2H), 3.09 (q, J = 5.7, 3.7 Hz, 2 H), 2.72 (s, 2H),2.27 (td, J = 9.5, 6.0 Hz, 2H), 1.70-1.61 (m, 2H), 1.41 (s, 9H), 1.22(d, J = 5.9 Hz, 3H). G-4-43

1-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]piperidine-4- carboxylic acid 464.58 (400 MHz,DMSO-d₆) δ 7.15 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.41-4.29(m, 2H), 3.61 (d, J = 12.5 Hz, 3H), 2.73 (t, J = 10.9 Hz, 2H), 2.63-2.55(m, 4H), 1.89 (d, J = 12.5 Hz, 2H), 1.71-1.56 (m, 2H), 1.46 (s, 1H),1.39 (s, 9H), 1.28-1.23 (m, 4 H), 1.04 (d, J = 6.0 Hz, 3H), 0.90-0.82(m, 1H)

4-([[(2R,3S)-3-[(Tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)benzoicacid (Intermediate G-4-20)

To a stirred solution of methyl4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)benzoate(215 mg, 0.55 mmol) in MeOH (9.00 mL) was added a solution of LiOH (131mg, 5.45 mmol) in H₂O (3.00 mL) at room temperature. The resultingmixture was stirred for 16 hours at room temperature. The mixture wasacidified to pH=6 with AcOH at 0° C. and purified by reversed phaseflash chromatography with the following conditions: Column: WelFlash™C18-I, 20-40 um, 120 g; Eluent A: water (plus 10 mmol/L AcOH); Eluent B:ACN; Gradient: 20%-40% B in 20 min; Flow rate: 50 mL/min; Detector: UV220/200 nm; desired fractions were collected at 32% B and concentratedunder reduced pressure to afford the title compound as a white solid(190 mg, 92%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 7.90 (d, J=7.8Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.21 (s, 1H), 6.70-6.61 (m, 2H), 4.56(d, J=4.3 Hz, 2H), 3.65-3.37 (m, 1H), 2.08-2.00 (m, 1H), 1.78 (s, 1H),1.50 (s, 1H), 1.37 (s, 9H), 1.09 (d, J=5.8 Hz, 3H); MS (ESI, m/z):[(M+23)]⁺=403.20.

The following intermediates in Table 41 were prepared according to theabove procedure to prepare Intermediate G-4-20.

TABLE 41 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMRG-4-21 

6-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]hexanoic acid 451.3  (400 MHz, CDCl₃) δ 7.25 (d, J= 7.8 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 6.70 (s, 1H), 6.41 (s, 1H),4.80 (d, J = 9.6 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 4.35 (d, J = 11.8Hz, 1H), 3.66 (s, 1H), 3.52 (d, J = 6.4 Hz, 1H), 2.65 (t, J = 6.9 Hz,2H), 2.39-2.22 (m, 4H), 1.91 (s, 1H), 1.66 (t, J = 7.4 Hz, 5H), 1.46 (s,9H), 1.38-1.28 (m, 2H), 1.21 (d, J = 6.2 Hz, 3H). G-4-22 

7-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]heptanoic acid 465.3  (400 MHz, CD₃OD) δ 7.28 (d,J = 7.8 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 4.56 (d, J = 11.4 Hz, 1H),4.49 (d, J = 11.5 Hz, 1H), 3.61-3.50 (m, 2H), 2.62 (t, J = 7.6 Hz, 2H),2.32-2.20 (m, 4H), 2.00 (s, 1H), 1.62 (q, J = 8.6, 7.1 Hz, 6H), 1.46 (s,9H), 1.42- 1.27 (m, 4H), 1.18 (d, J = 6.1 Hz, 3H). G-4-23 

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- (methylcarbamoyl)pentan-2- yl]oxy]methyl) phenyl]pentanoic acid 451.3  (400 MHz, CDCl₃) δ7.25 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.42 (s, 1H), 4.87(d, J = 9.6 Hz, 1H), 4.68-4.29 (m, 2H), 3.65-3.60 (m, 1H), 3.55 (q, J =5.1, 4.6 Hz, 1H), 2.82 (s, 3H), 2.65 (q, J = 5.4, 4.1 Hz, 2H), 2.36 (d,J = 6.8 Hz, 2H), 2.33-2.14 (m, 2H), 1.97 (q, J = 7.9, 7.2 Hz, 1H),1.75-1.60 (m, 5H), 1.45 (s, 9H), 1.19 (d, J = 6.2 Hz, 3H). G-4-24 

6-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]hex-5-ynoic acid 447.2  (400 MHz, DMSO-d₆) δ 12.14(br, 1H), 7.38-7.27 (m, 4H), 7.23 (s, 1H), 6.69 (s, 1H), 6.63 (d, J =9.1 Hz, 1H), 4.54-4.42 (m, 2H), 3.41 (dd, J = 14.9, 8.7 Hz, 2H),2.50-2.30 (m, 4H), 2.07-2.03 (m, 2H), 1.77 (m, 3H), 1.50-1.40 (m, 1H),1.38 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H). G-4-25 

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]pent-4-ynoic acid 433.2  (400 MHz, CD₃OD) δ7.38-7.28 (m, 4H), 4.58 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H),3.58 (ddd, J = 10.8, 5.2, 3.2 Hz, 1H), 3.56-3.46 (m, 1H), 2.70 (td, J =7.0, 1.4 Hz, 2H), 2.60 (td, J = 6.9, 1.3 Hz, 2H), 2.25 (tdd, J = 14.8,11.8, 7.8 Hz, 2H), 2.08-1.92 (m, 1H), 1.65-1.60 (m, 1H), 1.45 (s, 9H),1.18 (d, J = 6.2 Hz, 3H). G-4-26 

5-[3-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]pentanoic acid 437.3  (400 MHz, CD₃OD) δ 7.30-7.06(m, 4H), 4.63-4.41 (m, 2H), 3.75-3.44 (m, 2H), 2.65 (s, 2H), 2.43-2.15(m, 4H), 1.98 (ddd, J = 16.5, 8.8, 3.0 Hz, 1H), 1.76-1.54 (m, 5H), 1.46(s, 9H), 1.18 (d, J = 6.3 Hz, 3H). G-4-27 

6-[2-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl]hexanoic acid 451.2  (400 MHz, DMSO-d₆) δ 12.00(br, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.20-7.05 (m, 4H), 6.71-6.57 (m,2H), 4.55-4.40 (m, 2H), 3.45 (d, J = 6.9 Hz, 2H), 3.35-3.30 (m, 2H),2.59 (t, J = 7.9 Hz, 2H), 2.21 (t, J = 7.3 Hz, 2H), 2.04 (tt, J = 16.3,6.9 Hz, 2H), 1.85-1.75 (m, 1H), 1.55-1.40 (m, 5H), 1.39 (s, 9H), 1.08(d, J = 5.5 Hz, 3H). G-4-44 

3-[7-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) naphthalen-2- yl]propanoic acid 459.30 (400 MHz, DMSO-d₆)δ 12.09 (s, 1H), 7.84-7.80 (m, 2H), 7.76 (s, 1H), 7.68 (s, 1H),7.48-7.36 (m, 2H), 7.24 (s, 1H), 6.73-6.61 (m, 2H), 4.67-4.59 (m, 2H),3.48-3.44 (m, 2H), 3.01-2.97 (m, J = 7.6 Hz, 2H), 2.63 (m, J = 7.6 Hz,2H), 2.12- 2.05 (m, 2H), 1.88-1.77 (m, 1H), 1.64- 1.52 (m, 1H), 1.38 (s,9H), 1.10 (d, J = 5.9 Hz, 3H) G-4-45 

4-[6-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) naphthalen-2- yl]butanoic acid 473.15 (400 MHz, CD₃OD) δ7.83-7.75 (m, 3H), 7.65 (s, 1H), 7.49 (dd, J = 8.5, 1.6 Hz, 1H), 7.38(dd, J = 8.4, 1.7 Hz, 1H), 4.75 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.8Hz, 1H), 3.65-3.52 (m, 2H), 2.83 (t, J = 7.6 Hz, 2H), 2.40-2.18 (m, 4H),2.08-1.95 (m, 3H), 1.65 (dtd, J = 14.9, 9.6, 5.8 Hz, 1H), 1.40 (s, 9H),1.22 (d, J = 5.9 Hz, 3H) G-4-46 

3-[6-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) naphthalen-1- yl]propanoic acid 459.20 (400 MHz, DMSO-d₆)δ 12.12 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H),7.76 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 8.8, 1.8 Hz, 1H), 7.42 (t, J =7.6 Hz, 1H), 7.36 (d, J = 6.9 Hz, 1H), 7.24 (s, 1H), 6.72-6.63 (m, 2H),4.71-4.60 (m, 2H), 3.51-3.47 (m, 2H), 3.34-3.25 (m, 2H), 2.64 (t, J =7.7 Hz, 2H), 2.08-2.04 (m, 2H), 1.85-1.81 (m, 1H), 1.54-1.51 (m, 1H),1.37 (s, 9H), 1.11 (d, J = 5.8 Hz, 3H) G-4-47 

4-[6-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl) naphthalen-1- yl]butanoic acid 473.15 (400 MHz, DMSO-d₆)δ 12.11 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H),7.74 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 8.8, 1.8 Hz, 1H), 7.42 (dd, J =8.2, 7.0 Hz, 1H), 7.32 (dd, J = 7.1, 1.2 Hz, 1H), 7.23 (s, 1H),6.72-6.61 (m, 2H), 4.71-4.59 (m, 2H), 3.47 (dq, J = 11.8, 6.6, 6.0 Hz,2H), 3.05 (dd, J = 9.0, 6.7 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 2.09-2.06(m, 2H), 1.95-1.80 (m, 3H), 1.58-1.46 (m, 1H), 1.37 (s, 9H), 1.11 (d, J= 5.8 Hz, 3H). G-4-48 

(5E)-6-[4- ([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]hex-5- enoic acid [M + Na)]⁺ =472.15 Used in the next step without further purification G-4-49 

(4E)-5-[4- ([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]pent-4-enoic acid 435.20 (400MHz, DMSO-d₆) δ 12.07 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.26 (d, J =8.1 Hz, 2H), 7.23 (s, 1H), 6.69 (s, 1H), 6.62 (d, J = 9.1 Hz, 1H), 6.42(d, J = 16.0 Hz, 1H), 6.32-6.22 (m, 1H), 4.50-4.39 (m, 2H), 3.31 (s,3H), 2.42-2.38 (m, 3H), 2.14-1.97 (m, 1H), 1.81-1.77 (s, 1H), 1.38 (s,9H), 1.22-1.20 (m, 2H), 1.06 (d, J = 6.1 Hz, 3H) G-4-50 

[1-[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]piperidin-4- yl]acetic acid 478.30 (400 MHz,CD₃OD) δ 7.29-7.20 (m, 2H), 7.02-6.93 (m, 2H), 4.50 (d, J = 11.2 Hz,1H), 4.43 (d, J = 11.3 Hz, 1H), 3.68 (d, J = 12.2 Hz, 2H), 3.56 (s, 1H),3.60-3.45 (m, 1H), 2.75-2.68 (m, 2H), 2.33-2.17 (m, 4H), 2.09-1.95 (m,2H), 1.99-1.83 (m, 3H), 1.63-1.56 (m, 1H), 1.45 (s, 9H), 1.40 (dd, J =12.1, 3.6 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H) G-4-51 

3-[1-[4- ([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5-carbamoylpentan- 2- yl]oxy]methyl) phenyl]piperidin-4- yl]propanoic acid[(M − 1]⁻ = 490.30 (400 MHz, CD₃OD) δ 7.29-7.19 (d, J = 8.6 Hz, 2H),6.97 (d, J = 8.6 Hz, 2H), 4.46 (dd, J = 16.0, 32 Hz, 2H) 3.73-3.63 (m,2H), 3.58-3.48 (m, 2H), 2.68 (t, J = 12.0, 2H), 2.37 (t, J = 7.6 Hz,2H), 2.32-2.16 (m, 2H), 2.05-1.90 (m, 1H), 1.90-1.79 (m, 2H), 1.62 (q, J= 7.3 Hz, 3H), 1.45 (s, 9H), 1.41-1.31 (m, 2H), 1.16 (d, J = 6.2 Hz, 3H)G-4-52 

5-(4-[[(2S)-2- [(Tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]methyl]phenyl) pentanoic acid 423.15 (400 MHz, DMSO-d₆) δ 11.95 (s, 1H),7.22 (d, J = 7.9 Hz, 3H), 7.15 (d, J = 8.0 Hz, 2H), 6.70 (s, 1H), 6.66(d, J = 8.7 Hz, 1H), 4.42 (s, 2H), 3.56 (dq, J = 9.5, 4.5 Hz, 1H),3.38-3.35 (m, 2H), 3.34-3.23 (m, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.23 (t,J = 7.1 Hz, 2H), 2.12-2.01 (m, 2H), 1.80-1.67 (m, 1H), 1.62-1.43 (m,3H), 1.38 (s, 9H) G-4-53 

4-(4-[[(tert- butoxycarbonyl) amino]methyl] phenyl)butanoic acid [(M −1)]⁻ = 292.20 (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.36 (t, J = 6.2 Hz,1H), 7.15-7.12 (m, 4H), 4.09 (d, J = 6.1 Hz, 2H), 2.55 (t, J = 7.6 Hz,2H), 2.20 (t, J = 7.4 Hz, 2H), 1.77 (p, J = 7.5 Hz, 2H), 1.39 (s, 9H).G-4-54 

6-(4-[[(tert- butoxycarbonyl) amino]methyl] phenyl)hexanoic acid 322.20(400 MHz, DMSO-d₆) δ 11.96 (s, 1H), 7.33 (t, J = 6.3 Hz, 1H), 7.13 (s,4H), 4.08 (d, J = 6.0 Hz, 2H), 2.57-2.51 (m, 2H), 2.19 (t, J = 7.3 Hz,2H), 1.80-1.46 (m, 4H), 1.40 (s, 9H), 1.30-1.25 (m, 2H). G-4-55 

[4′-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl)- [1,1′-biphenyl]-3- yl]acetic acid 471.20 (400 MHz,DMSO-d₆) δ 7.61 (d, J = 8.2 Hz, 2H), 7.58-7.51 (m, 2H), 7.45-7.37 (m,3H), 7.25 (dt, J = 9.2, 2.3 Hz, 2H), 6.73- 6.61 (m, 2H), 4.60-4.48 (m,2H), 3.64 (s, 2H), 3.49-3.42 (m, 3H), 2.06-2.04 (m, 2H), 1.83-1.81 (m,1H), 1.56-1.45 (m, 1H), 1.39 (s, 9H), 1.09 (d, J = 5.9 Hz, 3H) G-4-56 

3-[[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]methyl] cyclobutane-1- carboxylic acid 449.25(400 MHz, CDCl₃) δ 7.25 (d, J = 7.8 Hz, 2H), 7.16-7.10 (m, 2H), 6.58 (s,1H), 6.01 (s, 1H), 4.90 (d, J = 9.7 Hz, 1H), 4.67-4.55 (m, 1H),4.46-4.34 (m, 1H), 3.73-3.48 (m, 2H), 3.00 (p, J = 9.1 Hz, 1H),2.84-2.66 (m, 2H), 2.61-2.20 (m, 5H), 2.14-1.89 (m, 3H), 1.67 (dd, J =28.1, 13.7 Hz, 1H), 1.46 (s, 9H), 1.21 (d, J = 6.1 Hz, 3H) G-4-57 

(3-[[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]methyl] cyclobutyl)acetic acid 463.40 (400 MHz,DMSO-d₆) δ 7.21 (dd, J = 8.1, 2.5 Hz, 3H), 7.10 (dd, J = 10.7, 7.9 Hz,2H), 6.68 (s, 1H), 6.61 (d, J = 9.1 Hz, 1H), 4.48-4.39 (m, 2H),3.54-3.48 (m, 1H), 3.48-3.35 (m, 1H), 2.69 (d, J = 7.8 Hz, 1H),2.64-2.51 (m, 2H), 2.40-2.24 (m, 4H), 2.18-2.04 (m, 3H), 2.04-1.95 (m,1H), 1.90-1.66 (m, 2H), 1.56-1.42 (m, 1H), 1.39 (s, 9H), 1.05 (s, 3H)G-4-58 

[3-[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]cyclobutyl] acetic acid 419.15 (400 MHz, CD₃OD)δ 7.30 (t, J = 8.0 Hz, 2H), 7.27-7.17 (m, 2H), 4.61-4.44 (m, 2H),3.67-3.57 (m, 1H), 3.57-3.47 (m, 1H), 3.48-3.35 (m, 1H), 2.77-2.51 (m,3H), 2.43 (d, J = 7.2 Hz, 1H), 2.39-2.14 (m, 4H), 2.07-1.93 (m, 1H),1.90-1.77 (m, 1H), 1.68-1.56 (m, 1H), 1.45 (s, 9H), 1.18 (s, 3H) G-4-59 

(4-[[4-([[(2R,3S)- 3-[(tert- butoxycarbonyl) amino]-5- carbamoylpentan-2- yl]oxy]methyl) phenyl]methyl] piperidin-1-yl)acetic acid 492.25 (400MHz, DMSO-d₆) δ 7.25-7.23 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H), 6.71 (s,1H), 6.62 (d, J = 9.1 Hz, 1H), 4.48-4.38 (m, 2H), 4.08 (d, J = 20.1 Hz,1H), 3.45-3.38 (m, 2H), 3.1-3.19 (m, 3H), 2.66-2.52 (m, 2H), 2.07-2.01(m, 2H), 1.80-1.76 (m, 1H), 1.69-1.56 (m, 4H), 1.52-1.41 (m, 2H), 1.40(s, 9H), 1.06 (d, J = 6.0 Hz, 3H) G-4-60 

3-(4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]propyl]phenyl) propanoic acid  422.522 (400 MHz, CD₃OD) δ 7.25-7.22 (m,1H), 7.22-7.10 (m, 4H), 4.27 (dd, J = 6.3, 1.7 Hz, 1H), 3.71-3.65 (m,1H), 3.51-3.35 (m, 4H), 2.95-2.87 (m, 3H), 2.71-2.56 (m, 4H), 2.31-2.26(m, 3H), 1.96-1.81 (m, 3H), 1.73-1.63 (m, 1H), 1.46 (s, 9H) G-4-61 

(4S)-4-[(tert- butoxycarbonyl) amino]-5-([[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-(([4- (4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]butyl)phenyl]methyl] (methyl)amino) pentanoic acid 849.30 (400 MHz,CD₃OD) δ 8.89 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.45-7.41 (m, 2H), 7.37(d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 4.65 (s, 1H), 4.57 (d, J= 7.6 Hz, 1H), 4.52 (s, 1H), 4.38 (d, J = 15.6 Hz, 1H), 4.14 (d, J =12.4 Hz, 1H), 3.94 (d, J = 8.7 Hz, 2H), 3.82 (dd, J = 11.0, 3.9 Hz, 1H),2.90 (s, 2H), 2.67 (s, 2H), 2.62 (s, 3H), 2.49 (s, 3H), 2.32-2.29 (m,3H), 2.14-2.01 (m, 2H), 1.99 (s, 2H), 1.85 (dd, J = 14.0, 6.3 Hz, 1H),1.70-1.58 (m, 5H), 1.48 (s, 9H), 1.05 (s, 9H) G-4-62 

10-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy] decanoicacid [(M − H)]⁻ = 401.10 (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 7.22 (s,1H), 6.78-6.52 (m, 1H), 3.53 (t, J = 6.7 Hz, 1H), 3.43-3.36 (m, 1H),3.29-3.13 (m, 1H), 2.21-2.17 (m, 2H), 2.09-1.99 (m, 1H), 1.85-1.56 (m,1H), 1.48 (q, J = 7.2 Hz, 5H), 1.38 (s, 8H), 1.31-1.21 (m, 15H). G-4-63 

9-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy] nonanoicacid 389.35 (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 7.21 (s, 1H), 6.68 (s,1H), 6.56 (d, J = 8.9 Hz, 1H), 3.52 (t, J = 6.7 Hz, 1H), 3.51- 3.48 (m,1H), 3.40-3.35 (m, 1H), 3.28- 3.14 (m, 2H), 2.21-2.15 (m, 6H), 2.11-2.00 (m, 2H), 1.79 (dt, J = 14.2, 6.8 Hz, 2H), 1.73-1.60 (m, 1H),1.56-1.43 (m, 7H), 1.37 (s, 9H). G-4-64 

(S)-8-((5-amino- 2-((tert- butoxycarbonyl) amino)-5- oxopentyl)oxy)octanoic acid 376.20 (400 MHz, DMSO-d₆) δ 7.23 (s, 1H), 6.69 (s, 1H)6.63-6.48 (m, 1H), 3.53 (t, J = 6.7 Hz, 1H), 3.45-3.13 (m, 4H),2.27-1.98 (m, 4H), 1.73-1.65 (m, 1H), 1.52-1.42 (m, 3H), 1.38 (s, 9H),1.32-1.21 (m, 8H) G-4-65 

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl)- 2- fluorophenyl] pentanoic acid 455.20 (400 MHz,DMSO-d₆) δ 11.87 (s, 1H), 7.26-7.18 (m, 2H), 7.08 (t, J = 11.0 Hz, 2H),6.71-6.61 (m, 2H), 4.51-4.39 (m, 2H), 3.47 (s, 1H), 3.41 (d, J = 11.7Hz, 1H), 2.59 (t, J = 7.1 Hz, 2H), 2.23 (t, J = 6.8 Hz, 2H), 2.11-1.99(m, 1H), 1.84-1.68 (m, 1H), 1.55-1.45 (m, 6H), 1.38 (s, 9H), 1.06 (d, J= 6.1 Hz, 3H) G-4-66 

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl)- 3- fluorophenyl] pentanoic acid 455.15 (400 MHz,DMSO-d₆) δ 7.34 (t, J = 7.9 Hz, 1H), 7.20 (s, 1H), 7.05-6.96 (m, 2H),6.67 (s, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.48 (q, J = 8.0 Hz, 2H),3.51-3.40 (m, 3H), 2.58 (t, J = 7.3 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H),2.14-1.92 (m, 3H), 1.85-1.70 (m, 1H), 1.63-1.43 (m, 4H), 1.38 (s, 9H),1.06 (d, J = 5.5 Hz, 3H) G-4-67 

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]butanoic acid 395.30 (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 7.26 (s,1H), 7.19 (dd, J = 9.0, 7.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.79-6.70(m, 4H), 3.87-3.83 (m, 2H), 3.66-3.57 (m, 1H), 2.58-2.54 (m, 2H), 2.21(t, J = 7.4 Hz, 2H), 2.15-2.11 (m, 2H), 1.87-1.73 (m, 3H), 1.65-1.61 (m,1H), 1.40 (s, 9H) G-4-87 

6-[5-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-chlorophenyl] hexanoic acid 457.30 (400 MHz, DMSO-d₆) δ 11.94 (m, 2H),7.28 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 3.0 Hz, 1H), 6.85-6.69 (m, 2H),3.85-3.83 (m, 2H), 3.73-3.69 (m, 1H), 2.64-2.62 (m, 2H), 2.19-2.17 (m,4H), 2.11-2.09 (m, J = 7.8 Hz, 2H), 1.63-1.52 (m, 5H), 1.50-1.46 (m,2H), 1.25 (s, 9H) G-4-88 

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 4-chlorophenyl] hexanoic acid 457.30 (300 MHz, DMSO-d₆) δ 11.97 (s, 1H),7.29 (d, J = 8.1 Hz, 2H), 7.01-6.98 (m, 1H), 6.83-6.72 (m, 1H),6.73-6.53 (m, 1H), 3.94-.91 (m, 2H), 2.57-2.35 (m, 2H), 2.22-2.19 (m,8H), 2.14-1.96 (m, 2H), 1.64-1.44 (m, 2H), 1.52 (s, 9H), 0.92-0.80 (m,2H) G-4-89 

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 5-chlorophenyl] hexanoic acid 457.10 (400 MHz, DMSO-d₆) δ 12.01 (s, 1H),7.27 (s, 1H), 6.88-6.79 (m, 3H), 6.77-6.72 (m, 2H), 4.48-4.34 (m, 1H),3.90-3.84 (m, 2H), 3.76-3.65 (m, 1H), 2.19 (d, J = 7.3 Hz, 2H),2.15-2.06 (m, 2H), 1.85-1.72 (m, 1H), 1.62-1.46 (m, 6H), 1.39 (s, 9H),1.30-1.24 (m, 2H) G-4-90 

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]hexanoic acid 423.30 (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 7.26 (s,1H), 7.17 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.76-6.72 (m,4H), 3.86-3.82 (m, 2H), 3.73-3.69 (m, 1H), 2.54 (d, J = 7.6 Hz, 2H),2.20 (t, J = 7.4 Hz, 2H), 2.14-2.10 (m, 2H), 1.88-1.75 (m, 1H),1.56-1.52 (m, 5H), 1.40 (s, 9H), 1.32-1.22 (m, 2H) G-4-91 

6-[4-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutanamido]phenyl]hexanoic acid 436.30 (300 MHz, DMSO-d₆) δ 11.88 (s, 1H), 9.84 (s,1H), 7.43-7.41 (m, 2H), 7.31-7.13 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H),6.87 (d, J = 7.5 Hz, 1H), 6.75 (s, 1H), 4.05-4.01 (m, 1H), 2.22-2.05 (m,4H), 1.97-1.67 (m, 2H), 1.60-1.47 (m, 5H), 1.38 (s, 9H), 1.35-1.20 (m,3H) G-4-92 

5-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]pentanoic acid 409.15 (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 7.27(s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.76-6.72(m, 4H), 3.86-3.82 (m, 2H), 3.72-3.68 (m, 1H), 2.55 (d, J = 7.0 Hz, 2H),2.28-2.07 (m, 4H), 1.67-1.43 (m, 6H), 1.39 (s, 9H) G-4-93 

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl)- 2- methylphenyl] pentanoic acid 451.25 (400 MHz,DMSO-d₆) δ 11.97 (s, 1H), 7.22 (s, 1H), 7.09-7.06 (m, 3H), 6.69 (s, 1H),6.60 (d, J = 9.2 Hz, 1H), 4.44-4.34 (m, 2H), 3.50-3.35 (m, 2H),2.56-2.54 (m, 3H), 2.27-2.23 (m, 6H), 2.12-1.97 (m, 2H), 1.83-1.75 (m,1H), 1.60-1.43 (m, 3H), 1.39 (s, 9H), 1.05 (d, J = 6.1 Hz, 3H) G-4-94 

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl)- 3- fluorophenyl] pentanoic acid 455.10 (400 MHz,DMSO-d₆) δ 11.91 (s, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (s, 1H), 7.04-6.96 (m, 2H), 6.66 (s, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.59-4.38 (m, 2H),3.44-3.39 (m, 2H), 2.59 (t, J = 7.4 Hz, 2H), 2.23 (t, J = 7.1 Hz, 2H),2.13-1.93 (m, 2H), 1.82-1.74 (m, 1H), 1.63-1.43 (m, 4H), 1.38 (s, 9H),1.35 (s, 1H), 1.07 (d, J = 5.6 Hz, 3H) G-4-95 

5-[4-([[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]methyl)- 3- methylphenyl] pentanoic acid 451.15 (400 MHz,Methanol-d₄) δ 7.22 (d, J = 7.6 Hz, 1H), 7.02-6.96 (m, 2H), 4.61-4.44(m, 2H), 3.60-3.53 (m, 2H), 2.64-2.56 (m, 2H), 2.37-2.17 (m, 7H),2.03-1.90 (m, 1H), 1.67-1.61 (m, 5H), 1.45 (s, 9H), 1.19 (d, J = 6.0 Hz,3H) G-4-113

4-[3-[(2S)-4- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-fluorophenyl] butanoic acid 413.30 (300 MHz, DMSO-d₆) δ 11.99 (s, 1H),7.29-7.27 (m, 1H), 7.06-6.97 (m, 2H), 6.88-6.79 (m, 2H), 6.76-6.74 (m,1H), 3.93 (d, J = 6.0 Hz, 2H), 3.75-3.70 (m, 1H), 2.64-2.59 (m, 2H),2.26-2.21 (m, 2H), 2.18-2.09 (m, 2H), 1.80-1.75 (m, 3H), 1.64-1.57 (m,1H), 1.39 (s, 9H) G-4-114

4-[3-[(2S)-4- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]2-fluoro-5- methylphenyl] butanoic acid 427.10 (300 MHz, DMSO-d₆) δ11.97 (s, 1H), 7.24 (s, 1H), 6.80 (d, J = 8.1 Hz, 2H), 6.71 (s, 1H),6.62-6.57 (m, 1H), 3.88 (d, J = 6.0 Hz, 2H), 3.77-3.65 (m, 1H),2.59-2.52 (m, 2H), 2.23 (s, 3H), 2.14-2.06 (m, 2H), 1.80-1.72 (m, 2H),1.47 (t, J = 7.1 Hz, 2H), 1.37 (s, 9H), 1.25 (p, J = 3.6 Hz, 2H) G-4-115

5-[3-[(2S)-4- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluoro-5- methylphenyl] pentanoic acid 441.20 (400 MHz, DMSO-d₆) δ11.97 (s, 1H), 7.27 (s, 1H), 6.87-6.77 (m, 2H), 6.74 (s, 1H), 6.61 (dd,J = 6.1, 2.0 Hz, 1H), 3.89 (d, J = 6.0 Hz, 2H), 3.77-3.68 (m, 1H),2.58-2.52 (m, 2H), 2.23 (s, 3H), 2.16-2.07 (m, 2H), 1.56-1.44 (m, 8H),1.39 (s, 9H) G-4-116

5-[4-[(4R)-4- [(tert- butoxycarbonyl) amino]-6- carbamoylhexyl]phenyl]pentanoic acid 421.30 (300 MHz, DMSO-d₆) δ 12.01 (s, 1H), 7.23(s, 1H), 7.09 (s, 4H), 6.69 (s, 1H), 6.60 (d, J = 9.0 Hz, 1H), 3.46-3.48(m, 1 H), 2.64-2.55 (m, 3 H), 2.23 (s, 2H), 2.03 (t, J = 7.9 Hz, 2H),1.53 (s, 11H), 1.39 (s, 9H) G-4-117

6-[6-[(1S)-1- amino-3- carbamoylpropyl] pyridin-3- yl]hexanoic acid294.15 (300 MHz, DMSO-d₆) δ 8.40-8.39 (d, J = 2.3 Hz, 1H), 7.67-7.64(dd, J = 8.0, 2.3 Hz, 1H), 7.28-7.16 (m, 2H), 6.70 (s, 1H), 3.81-3.77(m, 1H), 2.72-2.67 (t, J = 7.6 Hz, 2H), 2.21-2.17 (t, J = 7.3 Hz, 2H),2.13-1.90 (m, 2H), 1.87-1.75 (m, 2H), 1.68-1.63 (m, 2H), 1.56-1.49 (m,2H), 1.36-1.28 (m, 2H) G-4-118

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-chlorophenyl] butanoic acid 429.05 (400 MHz, DMSO-d₆) δ 12.00 (s, 1H),7.26 (s, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.03- 6.96 (m, 1H), 6.93-6.87(m, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 3.93 (d, J = 6.2 Hz,2H), 3.77 (s, 1H), 2.29-2.08 (m, 5H), 1.85-1.73 (m, 3H), 1.64-1.60 (m,1H), 1.50-1.46 (m, 1H), 1.39 (s, 9H) G-4-119

5-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-chlorophenyl] pentanoic acid 443.10 (400 MHz, DMSO-d₆) δ 12.00 (s, 1H),7.30-7.25 (m, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 8.3, 1.4 Hz,1H), 6.91 (dd, J = 7.6, 1.3 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.75 (s,1H), 3.92 (d, J = 6.1 Hz, 2H), 3.82-3.72 (m, 1H), 2.69 (t, J = 6.9 Hz,2H), 2.28-2.21 (m, 2H), 2.19-2.05 (m, 2H), 1.90-1.72 (m, 2H), 1.68-1.49(m, 4H), 1.39 (s, 9H) G-4-120

-[3-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-5-chloro-2- fluorophenyl] hexanoic acid 475.15 (300 MHz, DMSO-d₆) δ11.98 (s, 1H), 7.28 (s, 1H), 7.13-7.11 (m, 1H), 6.95-6.92 (m, 1H), 6.84(d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 4.01-3.86 (m, 2H), 3.74-3.71 (m, 1H),2.57 (t, J = 7.4 Hz, 2H), 2.13-2.09 (m, 2H), 1.81-1.77 (m, 1H),1.53-1.50 (m, 9H), 1.39 (s, 9H) G-4-121

5-(3-[2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutan- amido]-2-chlorophenyl) pentanoic acid 456.10 (400 MHz, DMSO-d6) δ 12.00 (s, 1H),9.32 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.68-7.51 (m, 1H), 7.25 (d, J =8.0 Hz, 1H), 7.14 (dd, J = 7.6, 1.6 Hz, 1H), 6.83- 6.78 (m, 1H), 4.12(s, 1H), 3.45 (s, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.25 (t, J = 6.6 Hz,2H), 2.20 (s, 2H), 1.87-1.73 (m, 1H), 1.58-1.54 (m, 5H), 1.41 (s, 9H)G-4-122

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]-2- chlorophenyl] butanoic acid 442.10 (400 MHz, DMSO-d₆) δ 12.08(s, 1H), 9.33 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.33-7.23 (m, 2H), 7.13(dd, J = 7.7, 1.6 Hz, 1H), 6.80 (s, 1H), 4.12 (s, 1H), 2.78- 2.70 (m,2H), 2.27 (t, J = 7.4 Hz, 2H), 2.19 (d, J = 9.2 Hz, 3H), 2.01-1.97 (m,1H), 1.86-1.73 (m, 3H), 1.41 (s, 9H) G-4-123

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutanamido]phenyl]butanoic acid 408.20 (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 9.89 (s,1H), 7.45 (dd, J = 8.3, 1.8 Hz, 2H), 7.29 (s, 1H), 7.25-7.18 (m, 1H),7.01 (d, J = 7.7 Hz, 1H), 6.91-6.86 (m, 1H), 6.77 (s, 1H), 4.03 (q, J =8.6, 8.1 Hz, 1H), 2.56-2.52 (m, 2H), 2.23-2.21 (m, 2H), 2.19-2.05 (m,2H), 1.96-1.84 (m, 1H), 1.79-1.71 (m, 3H), 1.39 (s, 9H) G-4-124

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]-2- chlorophenyl] hexanoic acid 470.20 (300 MHz, DMSO-d₆) δ 11.96(s, 1H), 9.59 (s, 1H), 7.78-7.70 (m, 1H), 7.31 (s, 1H), 7.18-6.95 (m,3H), 6.81 (s, 1H), 4.19-4.12 (m, 1H), 2.62 (t, J = 7.5 Hz, 2H),2.24-2.15 (m, 3H), 1.98-1.90 (m, 1H), 1.85-1.75 (m, 1H), 1.59-1.49 (m,4H), 1.40-1.29 (m, 12H) G-4-125

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]-2- fluorophenyl] hexanoic acid 454.20 (300 MHz, DMSO-d₆) δ 12.01(s, 1H), 9.33 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.32-7.24 (m, 3H),7.16-7.13 (m, 1H), 6.82 (s, 1H), 4.16-4.10 (m, 1H), 2.72 (t, J = 7.6 Hz,2H), 2.29-2.11 (m, 5H), 2.05- 1.96 (m, 1H), 1.90-1.73 (m, 1H), 1.63-1.51 (m, 5H), 1.42 (s, 9H) G-4-126

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluoro-6- methylphenyl] hexanoic acid 455.35 (400 MHz, DMSO-d₆) δ11.98 (s, 1H), 7.29-7.24 (m, 1H), 6.92-6.84 (m, 2H), 6.83 (d, J = 8.5Hz, 1H), 6.74 (s, 1H), 3.87 (d, J = 6.1 Hz, 2H), 3.74-3.70 (m, 1H),2.59-2.55 (m, 2H), 2.21 (s, 3H), 2.17-2.05 (m, 2H), 1.87-1.73 (m, 2H),1.65-1.43 (m, 6H), 1.39 (s, 9H), 1.35-1.31 (m, 2H) G-4-127

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2,6-difluorophenyl] hexanoic acid 459.15 (400 MHz, DMSO-d₆) δ 11.97 (s, 1H),7.27 (s, 1H), 7.06-7.02 (m, 1H), 6.98-6.94 (m, 1H), 6.83 (d, J = 8.5 Hz,1H), 6.74 (s, 1H), 3.98-3.87 (m, 2H), 3.73-3.69 (m, 1H), 2.60 (t, J =7.6 Hz, 2H), 2.19 (t, J = 7.3 Hz, 2H), 2.17-2.05 (m, 2H), 1.82-1.77 (m,1H), 1.61-1.55 (m, 1H), 1.56-1.46 (m, 4H), 1.38 (s, 9H), 1.32-1.28 (m,2H) G-4-128

[3-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]acetic acid 367.10 (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 7.35-7.10(m, 2H), 6.92-6.68 (m, 5H), 3.90-3.77 (m, 2H), 3.70-3.68 (m, 1H), 3.53(s, 2H), 2.21-2.05 (m, 2H), 1.89-1.74 (m, 1H), 1.66-1.55 (m, 1H), 1.40(s, 9H) G-4-129

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]-5- chlorophenyl] hexanoic acid [(M − 1)]⁻ = 468.25 (300 MHz,DMSO-d₆) δ 10.70 (s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 9.2 Hz,2H), 7.31 (t, J = 1.7 Hz, 1H), 6.89 (t, J = 1.7 Hz, 1H), 6.77 (s, 1H),4.01 (d, J = 6.7 Hz, 1H), 2.23-2.13 (m, 2H), 2.01-1.88 (m, 4H),1.62-1.42 (m, 5H), 1.36 (s, 9H), 1.33-1.19 (m, 4H) G-4-130

6-[3-[(2S)-2- [(Tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]-5- methylphenyl] hexanoic acid 450.20 (300 MHz, DMSO-d₆) δ 11.99(s, 1H), 9.79 (s, 1H), 7.32-7.22 (m, 3H), 7.00 (s, 1H), 6.84-6.72 (m,2H), 4.03 (q, J = 7.5, 7.0 Hz, 1H), 2.25 (s, 3H), 2.24-2.06 (m, 4H),1.96-1.82 (m, 2H), 1.62-1.48 (m, 6H), 1.40 (s, 9H), 1.38-1.29 (m, 2H)G-4-131

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]-2- methylphenyl] hexanoic acid 450.25 (400 MHz, DMSO-d₆) δ 11.98(s, 1H), 9.27 (s, 1H), 7.32 (s, 1H), 7.22-7.12 (m, 1H), 7.12-6.94 (m,3H), 6.89-6.74 (m, 1H), 4.07 (q, J = 7.6, 7.2 Hz, 1H), 2.65- 2.55 (m,2H), 2.20 (q, J = 6.9, 6.5 Hz, 4H), 2.10 (s, 3H), 1.99-1.95 (m, 1H),1.85-1.81 (m, 1H), 1.62-1.44 (m, 5H), 1.41 (s, 9H), 1.37-1.29 (m, 1H)G-4-132

3-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]propanoic acid 381.15 (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.27(s, 1H), 7.18 (t, J = 8.1 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.82-6.78(m, 2H), 6.75 (dd, J = 8.4, 2.5 Hz, 2H), 3.84 (qd, J = 9.6, 5.9 Hz, 2H),3.72 (tt, J = 9.2, 5.0 Hz, 1H), 2.79 (t, J = 7.6 Hz, 2H), 2.56- 2.52 (m,2H), 2.18-2.04 (m, 2H), 1.88- 1.75 (m, 1H), 1.66-1.54 (m, 1H), 1.40 (s,9H) G-4-133

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-fluorophenyl] butanoic acid 413.20 (400 MHz, DMSO-d₆) δ 12.05 (s, 1H),7.27 (s, 1H), 7.05-6.98 (m, 2H), 6.85-6.78 (m, 2H), 6.74 (s, 1H), 3.92(d, J = 6.0 Hz, 2H), 3.74-3.72 (m, 1H), 2.61 (t, J = 7.6 Hz, 2H), 2.23(t, J = 7.3 Hz, 2H), 2.14- 2.08 (m, 2H), 1.85-1.72 (m, 3H), 1.64- 1.53(m, 1H), 1.39 (s, 9H) G-4-134

5-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluorophenyl] pentanoic acid 427.15 (400 MHz, DMSO-d₆) δ 11.99 (s,1H), 7.28 (s, 1H), 7.01-6.98 (m, 2H), 6.84-6.82 (m, 2H), 6.74 (s, 1H),3.92 (d, J = 6.0 Hz, 2H), 3.75-3.71 (m, 1H), 2.59 (t, J = 6.9 Hz, 2H),2.23 (t, J = 6.9 Hz, 2H), 2.15- 2.11 (m, 2H), 1.87-1.78 (m, 1H), 1.60-1.47 (m, 5H), 1.39 (s, 9H) G-4-135

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]-5- fluorophenyl] hexanoic acid 454.25 (300 MHz, DMSO-d₆) δ 10.25(s, 1H), 7.46 (dt, J = 11.5, 2.2 Hz, 1H), 7.34 (s, 1H), 7.24-7.08 (m,2H), 6.92-6.58 (m, 2H), 4.03 (q, J = 7.5 Hz, 1H), 2.57-2.55 (m, 2H),2.20-2.08 (m, 4H), 1.90-1.78 (m, 2H), 1.61-1.49 (m, 4H), 1.39 (s, 9H),1.35-1.12 (m, 3H) G-4-136

6-[3-[2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutyl] amino)-2-fluorophenyl] hexanoic acid 441.20 (400 MHz, DMSO-d₆) δ 11.94 (s, 1H),7.25 (s, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.71(s, 1H), 6.60 (t, J = 8.2 Hz, 1H), 6.41 (t, J = 7.2 Hz, 1H), 5.23 (s,1H), 3.60 (s, 1H), 3.13-2.99 (m, 1H), 3.06-3.02 m, 2H), 2.55-2.51 (m,1H), 2.21-2.17 (m, 2H), 2.09-2.05 (m, 1H), 1.78-1.74 (m, 1H), 1.54-1.50(m, 5H), 1.39 (s, 9H), 1.33-1.29 (m, 3H) G-4-137

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-fluoro-5- methylphenyl] hexanoic acid 455.25 (400 MHz, DMSO-d₆) δ11.96 (s, 1H), 7.27 (s, 1H), 6.81 (dd, J = 12.3, 8.1 Hz, 2H), 6.74 (s,1H), 6.62 (dd, J = 6.0, 2.0 Hz, 1H), 3.89 (d, J = 6.0 Hz, 2H), 3.77-3.67 (m, 1H), 2.56-2.52 (m, 2H), 2.23 (s, 3H), 2.20 (t, J = 7.3 Hz, 2H),1.86-1.74 (m, 1H), 1.66-1.58 (m, 1H), 1.55-1.49 (m, 4H), 1.39 (s, 9H),1.36-1.22 (m, 4H) G-4-138

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2,5-difluorophenyl] hexanoic acid 459.20 (400 MHz, CD3OD) δ 6.80-6.73 (m,1H), 6.61-6.53 (m, 1H), 4.00 (d, J = 5.5 Hz, 2H), 3.94-3.86 (m, 1H),2.69-2.54 (m, 2H), 2.43-2.26 (m, 4H), 2.05-1.95 (m, 1H), 1.87-1.72 (m,1H), 1.70-1.59 (m, 4H), 1.46 (s, 9H), 1.46-1.34 (m, 2H) G-4-139

6-[2-[(1S)-3- carbamoyl-1-[(2- methylpropane-2- sulfinyl)amino]propyl]pyridin-4- yl]hexanoic acid 398.20 (300 MHz, DMSO-d₆) δ 8.42-8.40(d, J = 5.0 Hz, 1H), 7.30 (s, 1H), 7.22-7.10 (m, 2H), 6.8 (s, 1H),5.76-5.73 (d, J = 5.4 Hz, 1H), 4.27-4.21 (q, J = 6.4 Hz, 1H), 2.73- 2.68(t, J = 7.6 Hz, 2H), 2.25-1.98 (m, 5H), 1.95-1.78 (m, 1H), 1.66 (p, J =7.6 Hz, 2H), 1.54 (p, J = 7.4 Hz, 2H), 1.49- 1.27 (m, 3H), 1.10 (s, 9H)G-4-140

5-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutanamido]phenyl]pentanoic acid 422.25 (300 MHz, DMSO-d₆) δ 9.88 (s, 1H),7.46-7.43 (m, 2H), 7.30 (s, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.03-7.01 (m,1H), 6.90 (d, J = 7.9 Hz, 1H), 6.79 (s, 1H), 4.05- 4.01 (m, 1H),2.30-2.05 (m, 6H), 1.98- 1.74 (m, 3H), 1.62-1.52 (m, 4H), 1.41 (s, 9H)G-4-145

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-chloro-5- fluorophenyl] butanoic acid 447.10 (300 MHz, DMSO-d₆) δ12.10 (s, 1H), 7.28 (s, 1H), 6.99 (dd, J = 10.8, 2.7 Hz, 1H), 6.87-6.72(m, 3H), 3.97-3.93 (m, 2H), 3.78 (d, J = 5.2 Hz, 1H), 2.72 (t, J = 7.9Hz, 2H), 2.26 (t, J = 7.5 Hz, 2H), 2.15 (d, J = 6.9 Hz, 2H), 1.81 (q, J= 7.4 Hz, 3H), 1.63 (d, J = 13.1 Hz, 1H), 1.40 (s, 9H) G-4-146

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2,5-difluorophenyl] butanoic acid 431.20 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H),6.97 (t, J = 6.9 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H),6.71-6.65 (m, 1H), 3.94 (p, J = 9.7 Hz, 2H), 2.60-2.57 (m, 2H),2.22-2.17 (m, 2H), 2.12-2.08 (m, 2H), 1.77-1.69 (m, 3H), 1.53-1.50 (m,1H), 1.38 (s, 9H) G-4-147

4-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-2-chloro-5- methylphenyl] butanoic acid 443.05 (300 MHz, DMSO-d₆) δ11.99 (s, 1H), 7.28 (s, 1H), 6.90-6.65 (m, 3H), 3.91 (d, J = 6.1 Hz,2H), 3.85-3.65 (m, 1H), 2.66 (dd, J = 8.7, 6.6 Hz, 2H), 2.28 (s, 3H),2.24 (d, J = 7.3 Hz, 2H), 2.18-2.10 (m, 2H), 1.92-1.70 (m, 4H),1.69-1.56 (m, 1H), 1.40 (s, 9H)

The following intermediates in Table 42 were prepared according to Step4 to prepare Intermediate B.

TABLE 42 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H NMRG-4-29

6-[1-(2,6- Dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]hexanoic acid 374.2  (400 MHz, DMSO-d₆) δ 11.98 (br, 1H), 11.09 (s,1H), 7.07-6.96 (m, 2H), 6.86 (dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J =12.7, 5.4 Hz, 1H), 3.33 (s, 3H), 2.90 (ddd, J = 15.0, 12.3, 6.9 Hz, 1H),2.77-2.57 (m, 4H), 2.21 (t, J = 7.3 Hz, 2H), 2.05-1.97 (m, 1H),1.60-1.50 (m, 4H), 1.36-1.23 (m, 2H) G-4-30

7-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]heptanoic acid 388.1  (400 MHz, DMSO-d₆) δ 11.95 (br, 1H), 11.09 (s,1H), 7.07-6.96 (m, 2H), 6.86 (dd, J = 8.1, 1.6 Hz, 1H), 5.34 (dd, J =12.8, 5.3 Hz, 1H), 3.33 (s, 3H), 2.90 (ddd, J = 16.5, 13.0, 5.2 Hz, 1H),2.77-2.56 (m, 4H), 2.20 (t, J = 7.3 Hz, 2H), 2.07-1.93 (m, 1H), 1.58 (t,J = 6.4 Hz, 2H), 1.55-1.44 (m, 2H), 1.39-1.22 (m, 4H). G-4-31

8-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]octanoic acid 402.3  (400 MHz, DMSO-d₆) δ 11.98 (br, 1H), 11.10 (s,1H), 7.06-6.97 (m, 2H), 6.86 (dd, J = 8.0, 1.6 Hz, 1H), 5.34 (dd, J =12.8, 5.3 Hz, 1H), 3.33 (s, 3H), 2.91 (ddd, J = 17.0, 12.9, 5.2 Hz, 1H),2.72 (td, J = 13.0, 4.4 Hz, 1H), 2.67-2.53 (m, 4H), 2.06-1.96 (m, 1H),1.60 (d, J = 8.3 Hz, 2H), 1.49 (p, J = 7.3 Hz, 2H), 1.35-1.15 (m, 7H).G-4-32

8-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]octanoic acid 402.2  (400 MHz, DMSO-d₆) δ 12.00 (br, 1H), 11.10 (s,1H), 6.99-6.91 (m, 2H), 6.91-6.83 (m, 1H), 5.37 (dd, J = 12.5, 5.4 Hz,1H), 3.55 (s, 3H), 2.97-2.80 (m, 2H), 2.78-2.58 (m, 2H), 2.20 (t, J =7.3 Hz, 2H), 2.04-1.95 (m, 1H), 1.58 (q, J = 7.6 Hz, 2H), 1.50 (p, J =7.3 Hz, 2H), 1.41-1.33 (m, 7H). G-4-33

5-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]pentanoic acid 360.1  (400 MHz, DMSO-d₆) δ 11.93 (br, 1H), 11.09 (s,1H), 7.00-6.95 (m, 2H), 6.87 (dd, J = 5.8, 3.1 Hz, 1H), 5.37 (dd, J =12.4, 5.4 Hz, 1H), 3.56 (s, 3H), 2.98-2.85 (m, 3H), 2.79-2.57 (m, 2H),2.27 (d, J = 6.9 Hz, 2H), 2.04- 1.95 (m, 1H), 1.62 (s, 4H). G-4-68

7-3-(2,6- dioxopiperidin-3- yl)-1-methyl-2- oxo-1,3- benzodiazol-5-yl]heptanoic acid 388.10 (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 11.06 (s,1H), 7.06 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.90 (dd, J = 8.0, 1.5 Hz,1H), 5.34 (dd, J = 12.8, 5.3 Hz, 1H), 3.31 (s, 3H), 2.97-2.83 ( m, 1H),2.80- 2.70 (m, 1H), 2.60-2.53 (m, 2H), 2.18 (t, J = 7.3 Hz, 2H),2.04-1.95 (m, 1H), 1.54 (t, J = 7.5 Hz, 2H), 1.47 (q, J = 7.4 Hz, 2H),1.38-1.21 (m, 5H) G-4-69

5-(4-[[(tert- butoxycarbonyl) amino]methyl] phenyl)pentanoic acid 308.18(400 MHz, DMSO-d₆) δ 7.35 (t, J = 6.3 Hz, 1H), 7.13 (s, 4H), 4.08 (d, J= 6.2 Hz, 2H), 2.58-2.52 (m, 2H), 2.21 (t, J = 7.0 Hz, 2H), 1.61-1.45(m, 4H), 1.39 (s, 9H) G-4-70

6-[4-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]hexanoic acid 423.15 (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 7.26 (s,1H), 7.09 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.2 Hz, 3H), 6.73 (s, 1H),3.82 (qd, J = 9.6, 5.8 Hz, 2H), 3.70 (dp, J = 9.5, 5.1 Hz, 1H),2.26-2.02 (m, 6H), 1.86-1.81 (m, 1H), 1.68-1.45 (m, 5H), 1.39 (s, 9H),1.27 (p, J = 7.7, 7.2 Hz, 2H) G-4-71

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]phenyl]hexanoic acid 423.22 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H), 7.16 (t,J = 8.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.78-6.69 (m, 4H), 3.90- 3.80(m, 2H), 3.76-3.67 (m, 1H), 2.17 (t, J = 7.4 Hz, 2H), 2.12 (dd, J = 7.4,2.0 Hz, 1H), 2.09-2.05 (m, 3H), 1.88- 1.75 (m, 1H), 1.60-1.50 (m, 5H),1.39 (s ,9H), 1.32-1.25 (m, 3H) G-4-72

7-(3-methyl-1-(1- methyl-2,6- dioxopiperidin-3- yl)-2-oxo-2,3-dihydro-1H- benzo[d]imida- zol-5-yl)heptanoic acid 402.10 (400 MHz,CDCl₃) δ 6.92-6.83 (m, 2H), 6.70 (d, J = 8.0 Hz, 1H), 5.21 (dd, J =12.9, 5.3 Hz, 1H), 3.45 (s, 3H), 3.27 (s, 3H), 3.10-3.00 (m, 1H), 2.92-2.83 (m, 1H), 2.67 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.4 Hz, 4H),2.25-2.19 (m, 1H), 2.09-1.95 (m, 1H), 1.72-1.65 (m, 7H), 1.40-1.37 (m,2H) G-4-73

5-(3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]methyl]- phenyl)pentanoic acid 436.32 (400 MHz, DMSO-d₆) δ 8.28(t, J = 6.0 Hz, 1H), 7.28 (s, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.11-7.01(m, 3H), 6.94 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 4.26 (d, J = 5.6 Hz,2H), 3.94-3.88 (m, 1H), 3.17 (s, 2H), 2.20 (t, J = 7.0 Hz, 2H),2.13-2.07 (m, 2H), 1.90-1.83 (m, 1H), 1.76-1.69 (m, 1H), 1.61-1.44 (m,3H), 1.39 (s, 9H), 1.33-1.13 (m, 2H) G-4-74

6-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]hexanoic acid 374.20 (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 11.09 (s,1H), 6.99-6.91 (m, 2H), 6.91- 6.84 (m, 1H), 5.37 (dd, J = 12.5, 5.4 Hz,1H), 3.55 (s, 3H), 2.92-2.86 (m, 3H), 2.76-2.67 (m, 1H), 2.66-2.58 (m,1H), 2.23 (t, J = 7.3 Hz, 2H), 1.66-1.51 (m, 4H), 1.44-1.38 (m, 2H)G-4-75

7-1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]heptanoic acid 388.10 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 6.99-6.91(m, 2H), 6.91-6.83 (m, 1H), 5.37(dd, J = 12.5, 5.4 Hz, 1H), 3.55 (s,3H), 2.95-2.85 (m, 4H), 2.77-2.57 (m, 2H), 2.26-2.18 (m, 2H), 1.64-1.45(m, 4H), 1.43-1.30 (m, 4H) G-4-76

9-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]nonanoic acid 416.15 (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 11.10 (s,1H), 6.99-6.91 (m, 2H), 6.86 (dd, J = 5.2, 3.8 Hz, 1H), 5.37(dd, J =12.6, 5.4 Hz, 1H), 3.55 (s, 3H), 2.93- 2.84 (m, 3H), 2.83-2.55 (m, 3H),2.19 (t, J = 7.3 Hz, 2H), 1.62-1.56 (m, 2H), 1.49 (t, J = 7.2 Hz, 2H),1.42-1.30 (m, 4H), 1.30-1.25 (m, 4H) G-4-77

4-[1-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]azetidin-3- yl]btanoic acid 401.20 (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 6.98 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 6.34 (d, J = 8.4 Hz, 1H),5.31 (dd, J = 12.9, 5.3 Hz, 1H), 4.07 (t, J = 7.7 Hz, 2H), 3.56 (dd, J =15.8, 8.8 Hz, 2H), 3.31 (s, 3H), 2.93-2.88 (m, 1H), 2.81- 2.56 (m, 4H),2.24 (t, J = 7.2 Hz, 2H), 2.07-1.90 (m, 1H), 1.65-1.46 (m, 4H). G-4-78

4-[1-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]piperidin-4- yl]butanoic acid 429.35 (400 MHz, DMSO-d₆) δ 12.03 (s,1H), 11.12 (s, 1H), 7.77-6.54 (m, 3H), 5.38 (d, J = 12.0 Hz, 1H), 3.59(d, J = 11.4 Hz, 2H), 3.36 (s, 3H), 3.00-2.80 (m, 1H), 2.79-2.57 (m,2H), 2.24 (t, J = 7.3 Hz, 2H), 2.01 (dd, J = 9.6, 4.2 Hz, 1H), 1.97-1.75(m, 3H), 1.71-1.37 (m, 6H), 1.34-1.27 (m, 2H) G-4-79

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-fluorophenyl] hexanoic acid 441.51 (400 MHz, DMSO-d₆) δ 7.26 (s, 1H),7.05-6.93 (m, 2H), 6.86-6.77 (m, 2H), 6.73 (s, 1H), 3.91 (d, J = 6.0 Hz,2H), 3.17 (s, 1H), 2.59-2.55 (m, 2H), 2.55 (s, 3H), 2.18 (d, J = 7.3 Hz,2H), 2.14 (d, J = 7.3 Hz, 2H), 1.90-1.86 (m, 1H), 1.53-1.49 (m, 2H),1.39 (s, 9H), 1.35- 1.20 (m, 3H) G-4-96

6-[3-[(3R)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentyl]phenyl]hexanoic acid 421.35 (300 MHz, DMSO-d₆) δ 11.92 (s, 1H), 7.17(dt, J = 14.7, 4.6 Hz, 2H), 6.97 (d, J = 7.9 Hz, 3H), 6.67 (d, J = 8.8Hz, 2H), 3.38 (d, J = 7.5 Hz, 1H), 2.58- 2.52 (m, 2H), 2.19 (t, J = 7.3Hz,2H), 2.02 (t, J = 7.9 Hz, 2H), 1.62-1.54 (m, 8H), 1.40 (s, 9H),1.34-1.20 (m, 4H) G-4-97

(1r,4r)-4-[2-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]ethyl]cyclohex- ane-1-carboxylic acid 414.10 (400 MHz,DMSO-d₆) δ 11.96 (s, 1H), 11.08 (s, 1H), 7.05-6.97 (m, 2H), 6.90- 6.83(m, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 3.33 (s, 3H), 2.97-2.84 (m,1H), 2.78-2.70 (m, 1H), 2.66-2.57 (m, 3H), 2.22-2.07 (m, 1H), 2.03-1.97(m, 1H), 1.94-1.79 (m, 4H), 1.79-1.73 (m, 1H), 1.54-1.44 (m, 2H),1.36-1.27 (m, 1H), 1.28-1.14 (m, 3H) G-4-98

(1s,4s)-4-[2-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]ethyl]cyclohex- ane-1-carboxylic acid 414.20 (400 MHz,Chloroform-d) δ 8.28 (s, 1H), 6.88 (dd, J = 8.0, 1.6 Hz, 1H), 6.83 (d, J= 1.5 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.21 (dd, J = 12.6, 5.4 Hz,1H), 3.43 (s, 3H), 2.84-2.59 (m, 4H), 2.26-2.17 (m, 1H), 2.09-1.97 (m,2H), 1.90-1.82 (m, 4H), 1.70-1.51 (m, 5H), 1.29-1.25 (m, 2H) G-4-99

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxyl- 2-methylphenyl]- hexanoic acid [(M − l)]⁻ = 435.05 (400 MHz, DMSO-d₆) δ7.67-7.52 (m, 2H), 7.28 (s, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.82 (d, J =7.9 Hz, 1H), 6.73 (dd, J = 1.1, 3.7 Hz, 3H), 3.87-3.76 (m, 3H),2.56-2.53 (m, 2H), 2.19-2.12 (m, 3H), 2.09 (s, 3H), 1.89-1.75 (m, 2H),1.66-1.59 (m, 1H), 1.55-1.46 (m, 3H), 1.40 (s, 9H), 1.36-1.22 (m, 2H)G-4-100

6-[4-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-3-fluorophenyl] hexanoic acid [(M − 1)]⁻ = 439.10 (400 MHz, DMSO-d₆) δ7.67-7.53 (m, 3H), 7.29 (s, 1H), 7.11-6.98 (m, 3H), 6.88-6.69 (m, 3H),3.93 (d, J = 6.1 Hz, 2H), 3.76-3.72 (m, 1H), 2.55-2.51 (m, 1H),2.15-2.11 (m, 3H), 1.91-1.74 (m, 2H), 1.57-1.52 (m, 5H), 1.39 (s, 9H)G-4-101

6-(3-[[(2R,3S)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentan- 2-yl]oxy]phenyl) hexanoic acid 437.20 (400 MHz, DMSO-d₆) δ 7.31-7.22 (m,1H), 7.15 (t, J = 7.7 Hz, 1H), 6.80-6.65 (m, 5H), 4.33-4.27 (m, 1H),3.54-3.45 (m, 1H), 3.17 (s, 1H), 2.55-2.53 (m, 1H), 2.19-1.97 (m, 4H),1.91-1.82 (m, 1H), 1.58-1.47 (m, 5H), 1.39 (s, 9H), 1.34-1.21 (m, 3H),1.16 (d, J = 6.1 Hz, 3H) G-4-102

6-[5-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-methylphenyl] hexanoic acid 437.10 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H),7.01 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 6.69(d, J = 2.7 Hz, 1H), 6.64-6.62 (m, 1H), 3.80- 3.78 (m, 2H), 3.69-3.67(m, 3H), 2.27- 2.03 (m, 8H), 1.86-1.75 (m, 3H), 1.54- 1.52 (m, 5H), 1.39(s, 9H) G-4-103

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-5-methylphenyl] hexanoic acid [(M − 1)]⁻ = 435.05 (400 MHz, DMSO-d₆) δ7.39-7.16 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 6.56-6.50 (m,3H), 3.83-3.79 (m, 2H), 3.72-3.68 (m, 1H), 2.49-2.45 (m, 2H), 2.23 (s,3H), 2.21-2.06 (m, 3H), 1.87-1.74 (m, 1H), 1.57-1.50 (m, 5H), 1.39 (s,9H), 1.32-1.21 (m, 4H) G-4-104

6-[3-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-4-methylphenyl] hexanoic acid [(M − 1)]⁻ = 435.15 (400 MHz, DMSO-d₆) δ12.05 (s, 1H), 7.32-7.23 (m, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.80 (d, J =8.3 Hz, 1H), 6.75- 6.72 (m, 2H), 6.64 (d, J = 7.5, 1.5 Hz, 1H),4.03-3.69 (m,3H), 2.29-2.00 (m, 7H), 1.95-1.66 (m, 2H), 1.65-1.48 (m,6H), 1.39 (s, 9H), 1.30-1.26 (m, 2H) G-4-105

6-[5-[(2S)-2- [(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]- 2-fluorophenyl] hexanoic acid 441.10 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H),7.03 (t, J = 9.3 Hz, 1H), 6.86-6.79 (m, 2H), 6.77-6.73 (m, 2H),3.84-3.80 (m, 2H), 3.71-3.67 (m, 1H), 2.55 (t, J = 7.6 Hz, 2H), 2.18 (t,J = 7.3 Hz, 2H), 2.13- 2.09 (m, 2H), 1.87-1.74 (m, 1H), 1.64- 1.56 (m,1H), 1.54-1.50 (m, 4H), 1.39 (s, 9H), 1.33-1.20 (m, 2H) G-4-106

-[3-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy]-5-fluorophenyl] hexanoic acid 441.10 (400 MHz, DMSO-d₆) δ 12.00 (s, 1H),7.26 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H),6.64-6.54 (m, 3H), 3.92-3.80 (m, 2H), 3.73-3.69 (m, 1H), 2.54 (d, J =7.6 Hz, 2H), 2.24- 2.03 (m, 4H), 1.86-1.73 (m, 1H), 1.56- 1.52 (m, 4H),1.39 (s, 9H), 1.34-1.21 (m, 3H) G-4-107

6-(3-[(2S)-2- [tert- butoxycarbonyl) amino]-4- carbamoylbutan-amido]methyl] phenyl)hexanoic acid 450.25 (400 MHz, Methanol-d₆) δ 7.22(t, J = 7.5 Hz, 1H), 7.15 (s, 1H), 7.11-7.08 (m, 2H), 4.46-4.31 (m, 2H),4.11-4.04 (m, 1H), 2.69-2.54 (m, 2H), 2.32-2.28 (m, 4H), 2.15-2.04(m,1H), 1.91-1.89 (m, 1H), 1.72-1.56 (m, 4H), 1.46 (s, 9H), 1.41-1.32(m, 2H). G-4-108

6-[3-[(3R)-3- [(tert- butoxycarbonyl) amino]-5- carbamoylpentyl]phenyl]hexanoic acid 421.15 (400 MHz, DMSO-d₆) δ 11.91 (s, 1H), 7.21 (s,1H), 7.16 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 7.9 Hz, 3H), 6.69 (d, J =10.2 Hz, 2H), 3.44-3.34 (m, 1H), 2.56- 2.53 (m, 2H), 2.20 (t, J = 7.3Hz, 2H), 2.03 (t, J = 7.9 Hz, 2H), 1.69-1.47 (m, 10H), 1.41 (s, 9H),1.35-1.27 (m, 2H) G-4-141

tert-butyl N-(4- carbamoyl-1-[[2- fluoro-3-(4- hydroxybutyl)phenyl](methyl) amino]butan-2- yl)carbamate 412.15 (400 MHz, DMSO-d₆) δ7.22 (s, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.79 (t, J = 8.2 Hz, 1H), 6.71(dd, J = 15.4, 8.4 Hz, 2H), 6.56 (d, J = 9.0 Hz, 1H), 4.38 (s, 1H), 3.64(s, 1H), 3.41 (t, J = 6.4 Hz, 2H), 3.04 (d, J = 7.0 Hz, 2H), 2.78 (s,3H), 2.56 (t, J = 7.5 Hz, 2H), 2.17-1.96 (m, 2H), 1.91 (s, 1H),1.75-1.71 (m, 1H), 1.60-1.56 (m, 2H), 1.55 (s, 2H), 1.53 (s, 9H) G-4-142

4-[(1r,4s)-4-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]cyclohexyl] butanoic acid 428.20 Used next stepdirectly without purification G-4-143

4-[(1s,4r)-4-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]cyclohexyl] butanoic acid 428.25 (300 MHz, CD3OD) δ7.06 (s, 1H), 7.03-7.00 (m, 2H), 5.34-5.31 (m, 1H), 3.46-3.42 (m, 3H),2.97-2.75 (m, 3H), 2.59-2.55 (m, 1H), 2.29-2.26 (m, 2H), 2.22-2.13 (m,1H), 1.96-1.91 (m, 4H), 1.72-1.68 (m, 2H), 1.56-1.52 (m, 2H), 1.40-1.27(m, 3H), 1.16-1.32 (m, 2H) G-4-144

tert-butyl N- [(2S)-4- carbamoyl-1-[2- fluoro-3-(4- hydroxybutyl)phenoxy]butan-2- yl]carbamate 399.30 (400 MHz, DMSO-d₆) δ 7.27 (s, 1H),7.06-6.93 (m, 2H), 6.85-6.81 (m, 2H), 6.74 (s, 1H), 4.37 (s, 1H), 3.91(d, J = 6.1 Hz, 2H), 3.76-3.72 (m, 1H), 3.40 (t, J = 6.4 Hz, 2H), 2.59(t, J = 7.6 Hz, 2H), 2.21-2.03 (m, 2H), 1.88-1.75 (m, 2H), 1.67-1.51 (m,3H), 1.46-1.42 (m, 1H), 1.39 (s, 9H)

(7Z)-9-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-carbamoylbutoxy]non-7-eoicacid (Intermediate G-4-80)

To a solution of9-[(2S)-2-[(tert-butoxycarbonyl)amino]-4-carbamoylbutoxy]non-7-ynoicacid (400.00 mg, 1.040 mmol) in THF (10.00 mL) was added Lindlarcatalyst (429.70 mg, 0.104 mmol) and quinazoline (27.08 mg, 0.208 mmol)under nitrogen atmosphere. The mixture was hydrogenated at roomtemperature for 36 h under hydrogen atmosphere using a hydrogen balloon.It was filtered through a Celite pad. The filtrate was concentratedunder reduced pressure to give the title compound as an off-white solid(340 mg, 80%): ¹H NMR (400 MHz, DMSO-d₄) δ 11.96 (s, 1H), 7.22 (s, 1H),6.76-6.67 (m, 1H), 6.60 (d, J=8.8 Hz, 1H), 5.55-5.41 (m, 2H), 4.00-3.94(m, 2H), 3.28-3.03 (m, 2H), 2.28-2.13 (m, 3H), 2.08-1.99 (m, 4H),1.77-1.64 (m, 1H), 1.54-1.44 (m, 2H), 1.43-1.40 (m, 1H), 1.38 (s, 9H),1.37-1.23 (m, 4H). LC/MS (ESI, m/z): [(M+1)]⁺=387.20.

4-[1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]butanoicacid (Intermediate G-4-81)

To a stirred solution of3-[4-(4-hydroxybutyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione(1.09 g, 3.289 mmol) in CH₃CN (10.00 mL) and H₂O (10.00 mL) were added(acetyloxy)(phenyl)-lambda3-iodanyl acetate (2.33 g, 7.234 mmol) andTEMPO (0.13 g, 0.822 mmol) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for overnight at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by reversephase flash chromatography with the following conditions: Column:WelFlash™ C18-I, 20-40 um, 330 g; Eluent A: water (plus 10 mmol/L FA);Eluent B: ACN; Gradient: 15%-35% B in 20 min; Flow rate: 80 mL/min;Detector: UV 220/254 nm; desired fractions were collected at 28% B andconcentrated under reduced pressure to afford the title compound as awhite solid (900 mg, 79%):1H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H),11.09 (s, 1H), 6.98 (d, J=4.5 Hz, 2H), 6.91-6.84 (m, 1H), 5.37 (dd,J=12.5, 5.4 Hz, 1H), 3.56 (s, 3H), 2.96-2.83 (m, 3H), 2.78-2.66 (m, 1H),2.64 (d, J=5.2 Hz, 1H), 2.34 (t, J=7.1 Hz, 2H), 2.04-1.97 (m, 1H),1.89-1.78 (m, 2H); LC/MS (ESI, m/z): [(M+1)]⁺=346.05.

The intermediates in Table 43 were prepared according to the aboveprocedure to prepare Intermediate G-4-81.

TABLE 43 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-4-82

9-[(2S)-2-[(tert- butoxycarbonyl) amino]-4- carbamoylbutoxy] non-7-ynoicacid 385.15 (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 7.23 (s, 1H), 6.72 (s,1H), 6.63 (d, J = 8.7 Hz, 1H), 4.09 (t, J = 2.2 Hz, 2H), 3.50- 3.48 (m,1H), 3.35-3.28 (m, J = 8.4 Hz, 5H), 2.25-2.18 (m, J = 7.1, 3.4 Hz, 4H),2.06-2.02 (m, 2H), 1.80-1.62 (m, 1H), 1.48-1.39 (m, 4H), 1.38 (s, 9H)

4-[4-[1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]piperazin-1-yl]butanoicacid (Intermediate G-4-83)

Step 1. Tert-butyl4-[4-(1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-5-yl)piperazin-1-yl]butanoate.To a stirred solution of tert-butyl4-[4-(3-methyl-2-oxo-1H-1,3-benzodiazol-5-yl)piperazin-1-yl]butanoate(3.40 g, 9.079 mmol) in THF (70.00 mL) was added t-BuOK (1.53 g, 13.619mmol) at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 1 h at 0° C. under nitrogen atmosphere. To the above mixturewas added a solution of1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (4.50 g, 11.803 mmol) in THF (30.00 mL) at 0°C. under nitrogen atmosphere. The resulting mixture was stirred for 4 hat room temperature under nitrogen atmosphere. The reaction was quenchedwith sat. NH₄Cl (100 mL) at 0° C. The resulting mixture was extractedwith EtOAc (3×100 mL). The combined organic layers were washed withbrine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with EtOAc toafford the title compound as a dark blue solid (2.2 g, 40%): ¹H NMR (400MHz, DMSO-d₆) δ 7.25-7.14 (m, 2H), 6.90-6.79 (m, 4H), 6.60-6.55 (m, 1H),5.44 (dd, J=13.1, 5.4 Hz, 1H), 4.74 (s, 2H), 3.73 (s, 3H), 3.31 (s, 3H),3.15-3.02 (m, 6H), 2.85-2.78 (m, 1H), 2.75-2.65 (m, 1H), 2.56-2.51 (m,2H), 2.39-2.28 (m, 2H), 2.27-2.22 (m, 2H), 2.07-1.99 (m, 2H), 1.73-1.64(m, 2H), 1.41 (s 9H); LC/MS (ESI, m/z): [(M+1)]⁺=606.35.

The intermediates in Table 44 were prepared according to step 1 of theprocedure to prepare Intermediate G-4-83.

TABLE 44 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ‘H-NMR G-10-1

tert-butyl 3-[4- (1-[1-[(4- methoxyphenyl) methyl]-2,6-dioxopiperidin-3- yl]-3-methyl-2- oxo-1,3- benzodiazol-5-yl)piperazin-1- yl]propanoate 592.40 (400 MHz, DMSO-d₆) δ 7.25-7.17 (m,2H), 6.90- 6.79 (m, 4H), 6.60-6.54 (m, 1H), 5.44 (dd, J = 13.1, 5.4Hz,1H), 4.76 (s, 2H), 3.73 (s, 3H), 3.31 (s, 3H), 3.11-3.04 (m, 4H),2.87-2.67 (m, 4H), 2.60- 2.54 (m, 4H), 2.41 (t, J = 7.0 Hz, 2H),2.10-1.96 (m, 2H), 1.42 (s, 9H)

Step 2.4-[4-[1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]piperazin-1-yl]butanoicacid. To a stirred solution of tert-butyl4-[4-(1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-5-yl)piperazin-1-yl]butanoate(500.00 mg, 0.825 mmol) in toluene (50.00 mL) was added AlCl₃ (1100.65mg, 8.254 mmol) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for overnight at 90° C. under nitrogenatmosphere. The reaction was cooled down to room temperature andquenched with water (50 mL) at 0° C. The aqueous layer was extractedwith EtOAc (3×50 mL). The aqueous layer was purified by reverse phaseflash chromatography with the following conditions: Column: WelFlash™C18-I, 20-40 um, 330 g; Eluent A: water (plus 10 mmol/L FA); Eluent B:ACN; Gradient: 10%-30% B in 15 min; Flow rate: 80 mL/min; Detector: UV220/254 nm; desired fractions were collected at 17% B and concentratedunder reduced pressure to afford the title compound as a light yellowoil (210 mg, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 6.97 (d,J=8.6 Hz, 1H), 6.88 (s, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.30 (dd, J=12.9,5.4 Hz, 1H), 3.32 (s, 3H), 3.24-3.18 (m, 4H), 2.93-2.83 (m, 4H),2.76-2.57 (m, 4H), 2.31 (t, J=7.2 Hz, 2H), 2.11-1.87 (m, 2H), 1.86-1.72(m, 2H); LC/MS (ESI, m/z): [(M+1)]⁺=430.10

The intermediates in Table 45 were prepared according to step 2 of theprocedure to prepare Intermediate G-4-83.

TABLE 45 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR G-4-84

3-[4-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]piperazin-1- yl]propanoic acid 416.10 (400 MHz, DMSO-d₆) δ 11.06 (s,1H), 6.95 (d, J = 8.6 Hz, 1H), 6.85 (s, 1H), 6.63 (d, J = 8.6 Hz, 1H),5.30(dd, J = 12.9, 5.4 Hz, 1H), 3.34 (s, 3H), 3.12- 3.06 (m, 4H),2.97-2.83 (m, 2H), 2.76-2.58 (m, 8H), 2.45 (t, J = 7.1 Hz, 2H)

Step 5. (9H-fluoren-9-yl)methyl((3S,6S)-6-(((2R,3S)-6-amino-2-((4-(16-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-5-oxo-7,10,13-trioxa-4-azahexadecyl)benzyl)oxy)-6-oxohexan-3-yl)carbamoyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-yl)carbamate(Intermediate G). To a solution of (9H-fluoren-9-yl)methyl((3S,6S)-6-(((2R,3S)-6-amino-2-((4-(3-aminopropyl)benzyl)oxy)-6-oxohexan-3-yl)carbamoyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-yl)carbamatehydrochloride (300 mg, 0.39 mmol) in DMA (10.0 mL) were added2-(2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)ethoxy)aceticacid (179 mg, 0.39 mmol), TEA (118 mg, 1.17 mmol) and HATU (190 mg, 0.50mmol) at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 16 hours at room temperature under nitrogen atmosphere. Themixture was concentrated under reduced pressure. The residue waspurified by reversed phase flash chromatography with the followingconditions: column, C18 silica gel; Mobile phase A: water (plus 10mmol/L AcOH); Mobile phase B: CAN. Gradient (B %): 40% to 60% in 20 min;Detector: UV 254/220 nm; desired fractions were collected at 58% B andconcentrated under reduced pressure to afford the title compound as awhite solid (229 mg, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.92-7.85 (m, 3H), 782-7.74 (m, 3H), 7.43 (t, J=7.4 Hz, 2H), 7.34 (t,J=7.4 Hz, 2H), 7.23-7.14 (m, 3H), 7.13-7.04 (m, 3H), 7.06-6.93 (m, 4H),6.85 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 5.76 (s, 1H), 5.33 (dd, J=12.6,5.4 Hz, 1H), 5.05 (d, J=10.5 Hz, 1H), 4.39 (s, 2H), 4.25 (d, J=7.0 Hz,2H), 3.88 (s, 2H), 3.58 (s, 3H), 3.56-3.47 (m, 3H), 3.42 (d, J=5.5 Hz,2H), 3.40-3.34 (m, 12H), 3.31 (s, 2H), 3.10 (s, 2H), 2.86 (s, 2H),2.68-2.52 (m, 4H), 2.08 (s, 6H), 1.69 (s, 4H), 1.06 (d, J=6.2 Hz, 3H);MS (ESI, m/z): [(M+1)]⁺=1189.70.

The following intermediates in Table 46 were prepared according to Step5 above to prepare Intermediate G.

TABLE 46 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H NMR G1

(9H-fluoren-9- yl)methyl N- [(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propanamido] propyl)phenyl] methoxy]pentan-3-yl]carbamoyl]- 12-oxo-1-azatricyclo [6.4.1.0{circumflex over( )}[4,13]]tri- deca-4(13),5,7-trien- 11-yl]carbamate 1057.6 (400 MHz,DMSO-d₆) δ 7.91 (d, J = 7.5 Hz, 2H), 7.87 (d, J = 6.0 Hz, 2H), 7.76 (t,J = 7.1 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H),7.33-7.14 (m, 3H), 7.10-7.03 (m, 4H), 7.00 (d, J = 8.2 Hz, 1H), 5.33(dd, J = 13.0, 5.4 Hz, 1H), 5.06 (d, J = 10.9 Hz, 1H), 4.41 (s, 2H),4.27 (t, J = 6.3 Hz, 2H), 4.13 (s, 1H), 3.44 (d, J = 5.9 Hz, 2H), 3.10-2.98 (m, 3H), 2.90-2.80 (m, 3H), 2.70-2.56 (m, 2H), 2.41 (t, J = 7.7 Hz,2H), 2.1-2.00 (m, 4H), 1.78 (s, 1H), 1.64 (q, J = 7.4 Hz, 2H), 1.08 (d,J = 6.2 Hz, 3H). G2

(9H-fluoren-9- yl)methyl N- [(2S)-1- [(1R,2S,5S)-2- [[(3S,4R)-1-carbamoyl-4-[[4- (3-[2-[2-(2-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro- 1H-1,3- benzodiazol-5-yl]propoxy]ethoxy) ethoxy]acetamido] propyl)phenyl] methoxy]pentan-3-yl]carbamoyl]- 3- azabicyclo[3.1.0] hexan-3-yl]-1- oxohexan-2-yl]carbamate 1183.8 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.90 (d, J = 7.5Hz, 2H), 7.80-7.65 (m, 3H), 7.59 (dd, J = 12.1, 8.3 Hz, 2H), 7.42 (t, J= 7.5 Hz, 2H), 7.33 (t, J = 7.1 Hz, 2H), 7.30-7.20 (m, 3H), 7.14 (d, J =7.8 Hz, 2H), 7.08-6.97 (m, 3H), 6.86 (d, J = 7.8 Hz, 1H), 4.50- 4.33 (m,3H), 4.29-4.19 (m, 2H), 3.88 (s, 3H), 3.60-3.46 (m, 5H), 3.42-3.35 (m,3H), 3.35-3.29 (m, 6H), 3.11 (q, J = 6.7 Hz, 2H), 2.76-2.58 (m, 5H),2.54 (s, 2H), 2.10-2.04 (m, 9H), 1.87-1.67 (m, 6H), 1.52 (s, 3H),1.33-1.22 (m, 4H), 1.08 (d, J = 6.1 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H),0.56 (s, 2H). G3

(9H-fluoren-9- yl)methyl N- [(2S)]-1- [(1R,2S,5S)-2- [[(3S,4R)-1-carbamoyl-4-[(4- [3-[2-(2-[3-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro- 1H-1,3- benzodiazol-5- yl]propoxy]ethoxy)acetamido]propyl] phenyl)methoxy] pentan-3- yl]carbamoyl]-3-azabicyclo[3.1.0] hexan-3-yl]-1- oxohexan-2- yl]carbamate 1139.8 (400MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.75-7.70 (d, J= 6.2 Hz, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.34(d, J = 7.4 Hz, 2H), 7.32-7.20 (m, 3H), 7.16-7.10 (m, 3H), 7.08-6.97 (m,3H), 6.87 (d, J = 8.5 Hz, 1H), 6.67 (s, 1H), 5.34 (dd, J = 12.6, 5.3 Hz,1H), 4.47 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 11.3 Hz, 1H), 4.36 (d, J =5.5 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.22 (d, J = 6.5 Hz, 2H), 4.10(d, J = 6.7 Hz, 1H), 3.90 (s, 2H), 3.87 (s, 1H), 3.71 (s, 1H), 3.62-3.53 (m, 6H), 3.44-3.35 (m, 3H), 3.12 (q, J = 6.8 Hz, 2H), 2.90 (t, J =14.9 Hz, 1H), 2.77-2.59 (m, 3H), 2.54 (d, J = 1.9Hz, 9H), 2.11 (d, J =8.1 Hz, 2H), 2.08 (s, 2H), 1.87-1.79 (m, 2H), 1.77- 1.67 (m, 3H), 1.52(s, 3H), 1.33- 1.22 (m, 4H), 1.08 (d, J = 6.2 Hz, 3H), 0.87 (d, J = 7.2Hz, 2H). G4

(9H-fluoren-9- yl)methyl N- [(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[15-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]-3,6,9,12- tetraoxapenta- decanamido]propyl)phenyl]methoxy] pentan-3- yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0]{circumflex over ( )}[4,13]trideca- 4(13),5,7-trien- 11-yl]carbamate1233.7 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.95-7.81 (m, 3H), 7.81- 7.69(m, 4H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.20-6.92(m, 10H), 6.86 (d, J = 7.9 Hz, 1H), 6.70 (s, 1H), 5.34 (dd, J = 12.7,5.4 Hz, 1H), 5.06 (d, J = 10.4 Hz, 1H), 4.40 (s, 2H), 4.32-4.23 (m, 2H),4.13 (s, 1H), 3.87 (s, 2H), 3.81-3.75 (m, 1H), 3.68-3.53 (m, 9H), 3.54-3.41 (m, 6H), 3.44-3.35 (m, 1H), 3.32 (s, 3H), 3.21-3.08 (m, 3H), 3.05(s, 1H), 2.86 (t, J = 14.4 Hz, 2H), 2.76-2.52 (m, 8H), 2.11- 2.06 (m,3H), 2.01 (s, 2H), 1.88- 1.73 (m, 4H), 1.56 (s, 1H), 1.07 (d, J = 6.3Hz, 3H). G5

(9H-fluoren-9- yl)methyl N- [(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[2-(2-[3-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propoxy]ethoxy) acetamido]propyl]phenyl)methoxy] pentan-3- yl]carbamoyl]- 12-oxo-1- azatricyclo-[6.4.1.0{circumflex over ( )}[4,13]]trideca- 4(13),5,7-trien-11-yl]carbamate 1145.8 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.94-7.81 (m,3H), 7.80- 7.65 (m, 3H), 7.46-7.31 (m, 4H), 7.25-7.12 (m, 3H), 7.09 (dd,J = 8.0, 3.5 Hz, 2H), 7.06-6.97 (m, 4H), 6.93 (dd, J = 15.1, 7.7 Hz,1H), 6.85 (dd, J = 8.2, 1.5 Hz, 1H), 6.70 (s, 1H), 6.28 (s, 1H), 5.33(dd, J = 12.7, 5.3 Hz, 1H), 5.09-5.02 (m, 1H), 4.39 (s, 2H), 4.29 (s,2H), 4.12 (s, 1H), 3.89 (s, 2H), 3.77 (s, 1H), 3.70-3.57 (m, 4H),3.50-3.38 (m, 5H), 3.37-3.25 (m, 3H), 3.12 (q, J = 6.7 Hz, 2H),3.07-2.99 (m, 1H), 2.95-2.80 (m, 2H), 2.74-2.60 (m, 4H), 2.54 (d, J =7.5 Hz, 2H), 2.15-1.99 (m, 6H), 1.92-1.65 (m, 5H), 1.53 (s, 1H), 1.07(dd, J = 6.1, 1.8 Hz, 3H). G6

(9H-fluoren-9- yl)methyl N- [(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(2-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propoxy] acetamido)propyl] phenyl]methoxy)pentan-3- yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )} [4,13]]trideca- 4(13),5,7-trien- 11-yl]carbamate 1101.7 (400 MHz,DMSO-d6) δ 11.09 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.88 (dd, J = 19.4,8.4 Hz, 2H), 7.39 (dt, J = 34.0, 7.4 Hz, 3H), 7.22-7.07 (m, 5H),7.07-6.93 (m, 4H), 6.93-6.85 (m, 1H), 6.71 (s, 1H), 5.34 (dd, J = 12.6,5.3 Hz, 1H), 5.05 (d, J = 10.7 Hz, 1H), 4.40 (s, 2H), 4.31-4.20 (m, 2H),3.96-3.82 (m, 3H), 3.52-3.41 (m, 3H), 3.22-3.07 (m, 3H), 2.86 (t, J =15.2 Hz, 2H), 2.76-2.61 (m, 3H), 2.61-2.51 (m, 9H), 2.14- 2.04 (m, 7H),1.94-1.83 (m, 2H), 1.72 (q, J = 7.4 Hz, 3H), 1.55 (s, 1H), 1.08 (d, J =6.2 Hz, 3H). G7

9H-fluoren-9- ylmethyl N- [(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[2-[2-(2-[3-[3- methyl-1-(1- methyl-2,6- dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]propoxy]ethoxy) ethoxy]acetamido]propyl)phenyl] methoxy]pentan- 3-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0]{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien- 11-yl]carbamate 1203.9 (400 MHz, DMSO-d₆) δ 7.90 (d, J= 7.6 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.74 (dt, J = 15.1, 6.9 Hz,4H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.16 (d, J =6.9 Hz, 3H), 7.13-6.92 (m, 7H), 6.85 (dd, J = 8.2, 1.5 Hz, 1H), 6.69 (s,1H), 5.40 (dd, J = 13.0,5.3 Hz, 1H), 5.06 (d, J = 11.0 Hz, 1H), 4.40 (s,2H), 4.27 (t, J = 6.3 Hz, 2H), 4.13 (s, 1H), 3.88 (s, 2H), 3.78 (s, 1H),3.61- 3.49 (m, 6H), 3.53-3.43 (m, 2H), 3.46-3.35 (m, 3H), 3.32 (s, 5H),3.12 (q, J = 6.7 Hz, 2H), 3.03 (s, 3H), 3.02-2.91 (m, 1H), 2.85 (d, J =16.7 Hz, 1H), 2.77-2.60 (m, 4H), 2.55 (d, J = 8.0Hz, 3H), 2.08 (s, 6H),2.12-1.96 (m, 1H), 1.76 (dp, J = 39.7, 6.9 Hz, 4H), 1.55 (s, 1H), 1.07(d, J = 6.2 Hz, 3H). G8

9H-fluoren-9- ylmethyl N- [(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[2-(2-[3-[3- methyl-1-(1- methyl-2,6- dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]propoxy]ethoxy) acetamido]propyl]phenyl)methoxy] pentan-3- yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien- 11-yl]carbamate 1159.9 (400 MHz, DMSO-d₆) δ 7.90 (d, J= 7.5 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.75 (dd, J = 12.7, 6.7 Hz,4H), 7.43 (t, J = 7.3 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.16 (d, J =7.4 Hz, 3H), 7.10 (d, J = 7.8 Hz, 2H), 7.07-7.01 (m, 3H), 6.99 (dd, J =14.3, 7.7 Hz, 2H), 6.85 (dd, J = 8.0, 1.6 Hz, 1H), 6.69 (s, 1H), 5.76(s, 4H), 5.40 (dd, J = 13.0, 5.3 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H),4.39 (s, 2H), 4.27 (t, J = 6.4 Hz, 3H), 4.13(s, 1H), 3.90 (s, 2H), 3.78(s, 2H), 3.64- 3.51 (m, 5H), 3.43 (q, J = 6.0 Hz, 4H), 3.13 (q, J = 6.6Hz, 3H), 3.03 (s, 4H), 3.01-2.91 (m, 1H), 2.89-2.77 (m, 2H), 2.77-2.61(m, 4H), 2.55 (d, J = 7.9 Hz, 2H), 2.11-1.96 (m, 1H), 1.83 (p, J = 6.6Hz, 2H), 1.71 (p, J = 7.4 Hz, 2H), 1.55 (d, J = 11.2 Hz, 1H), 1.07 (d, J= 6.2 Hz, 3H). G9

9H-fluoren-9- ylmethyl N- [(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]propoxy]propyl) phenyl]methoxy] pentan-3- yl]carbamoyl]- 12-oxo-1-azatricyclo- [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien- 11-yl]carbamate 1183.8 (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 7.90 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.74 (q, J =8.0, 7.5 Hz, 3H), 7.42 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H),7.14 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H), 6.99- 6.91 (m, 3H),6.90-6.84 (m, 1H), 6.68 (s, 1H), 5.36 (dd, J = 12.6, 5.4 Hz, 1H), 5.06(d, J = 10.5 Hz, 1H), 4.41 (s, 2H), 4.27 (dd, J = 12.6, 6.9 Hz, 2H),4.12 (s, 1H), 3.78(s, 3H), 3.57 (d, J = 9.7 Hz, 7H), 3.40 (dt, J = 19.8,6.2 Hz, 5H), 3.06 (d, J = 14.5 Hz, 1H), 2.97 (t, J = 7.8 Hz, 2H), 2.86(d, J = 16.6 Hz, 2H), 2.77- 2.66 (m, 2H), 2.66-2.58 (m, 3H), 2.18-2.08(m, 10 H), 2.01 (s, 3H), 1.82 (dt, J = 15.2, 7.6 Hz, 6H), 1.55 (s, 2H),1.35-1.23 (m, 4H), 1.08 (d, J = 6.2 Hz, 3H).

Tert-butylN-[(3S,4R)-1-carbamoyl-4-[[4-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]methyl)phenyl]methoxy]pentan-3-yl]carbamate(Intermediate G10)

To a solution of(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidehydrochloride (302 mg, 0.65 mmol) in DMA (3.00 mL) were added[4-([[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]aceticacid (150 mg, 0.38 mmol), TEA (154 mg, 1.52 mmol) and HATU (188 mg, 0.49mmol) at 25° C. under nitrogen atmosphere. After stirring for additional1 hour, the resulting mixture was purified by reversed phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 330 g; Eluent A: water (plus 10 mmol/L AcOH); Eluent B: ACN;Gradient: 35%-55% B in 25 min; Flow rate: 80 mL/min; Detector: UV254/220 nm; desired fractions were collected at 46% B and concentratedunder reduced pressure to afford the title compound as a white foam (200mg, 65%): ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 7.66 (s, 1H),7.41-7.25 (m, 6H), 7.21 (d, J=7.4 Hz, 2H), 6.43-6.11 (m, 2H), 5.82 (s,1H), 4.83 (d, J=9.2 Hz, 1H), 4.69 (s, 1H), 4.65-4.44 (m, 4H), 4.44-4.27(m, 2H), 4.02 (d, J=11.0 Hz, 1H), 3.74-3.52 (m, 4H), 2.52 (s, 3H), 2.44(s, 1H), 2.23 (s, 2H), 2.14 (d, J=9.3 Hz, 1H), 2.01 (s, 3H), 1.66 (s,1H), 1.43 (s, 9H), 1.18 (d, J=5.7 Hz, 3H), 0.87 (s, 9H); MS (ESI, m/z):[(M+1)]⁺=807.35.

The following intermediates in Table 47 were prepared according to theabove procedure to prepare Intermediate G10.

TABLE 47 Characterization data for intermediates prepare according tothe procedure above. Inter- MS: me- [(M + diate Structure Chemical Name1)]⁺ ¹H-NMR G11

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]phenyl) methoxy]pentan-3- yl]carbamate 793.5 (400 MHz,DMSO-d₆) δ 8.99 (d, J = 3.9 Hz, 1H), 8.59 (s, 1H), 7.93 (d, J = 9.0 Hz,1H), 7.85 (d, J = 7.5 Hz, 2H), 7.44-7.41 (m, 6H), 7.22 (s, 1H),6.71-6.61 (m, 2H), 5.15 (s, 1H), 4.78 (dd, J = 9.1, 3.0 Hz, 1H), 4.55(d, J = 3.4 Hz, 2H), 4.47 (t, J = 6.3 Hz, 1H), 4.43 (dd, J = 14.0, 4.5Hz, 1H), 4.38 (s, 2H), 4.25 (dd, J = 15.3, 5.6 Hz, 1H), 3.74 (s, 2H),3.33 (s, 1H), 2.46-2.42 (m, 3H), 2.06 (s, 4H), 1.91 (d, J = 2.9 Hz, 3H),1.79 (s, 1H), 1.49 (s, 1H), 1.38 (s, 9H), 1.11-0.98 (m, 12H). G12

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(2- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]ethyl) phenyl]methoxy]pentan- 3-yl]carbamate 821.6 (400MHz, CDCl₃) δ 8.71 (s, 1H), 7.42-7.32 (m, 5H), 7.22 (d, J = 7.9 Hz, 2H),7.14 (d, J = 7.8 Hz, 2H), 6.36 (d, J = 9.1 Hz, 1H), 5.73 (s, 1H), 4.95(d, J = 9.7 Hz, 1H), 4.70 (t, J = 7.9 Hz, 1H), 4.61-4.52 (m, 4H),4.41-4.33 (m, 2H), 4.06 (d, J = 11.4 Hz, 1H), 3.70-3.51 (m, 3H),3.02-2.86 (m, 2H), 2.53-2.52 (m, 5H), 2.24 (t, J = 7.0 Hz, 2H), 2.17(t,J = 10.6 Hz, 1H), 2.00-1.90 (m, 1H), 1.72-1.58 (m, 1H), 1.44 (s, 9H),1.19 (d, J = 6.3 Hz, 3H), 0.90 (s, 9H). G13

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[3- ([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methoxy) propyl]phenyl] methoxy)pentan-3- yl]carbamate865.6 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.61 (t, J = 6.0 Hz, 1H), 7.45-7.36 (m, 5H), 7.23-7.13 (m, 5H), 6.67 (s, 1H), 6.59 (d, J = 9.0 Hz, 1H),5.16 (d, J = 3.5 Hz, 1H), 4.57 (d, J = 9.5 Hz, 1H), 4.49-4.34 (m, 5H),4.26 (dd, J = 15.9, 5.6 Hz, 1H), 3.93 (s, 2H), 3.70-3.59 (m, 2H),3.50-3.37 (m, 4H), 2.65 (t, J = 7.8 Hz, 2H), 2.43 (s, 3H), 2.12-1.74 (m,8H), 1.38 (s, 9H), 1.05 (d, J = 6.0 Hz, 3H), 0.95 (s, 9H). G14

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[3- (II(2S)-1-[(2S,4S)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methoxy) propyl]phenyl] methoxy)pentan-3- yl]carbamate865.6 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.68 (t, J = 6.1 Hz, 1H), 7.45-7.35 (m, 5H), 7.27-7.15 (m, 4H), 7.15 (d, J = 7.8 Hz, 2H), 6.67 (s, 1H),6.59 (d, J = 9.1 Hz, 1H), 5.45 (d, J = 7.3 Hz, 1H), 4.53 (d, J = 9.3 Hz,1H), 4.41 (s, 2H), 4.48-4.35 (m, 1H), 4.33-4.20 (m, 2H), 3.99-3.85 (m,3H), 3.65 (s, 1H), 3.51-3.43 (m, 4H), 2.63 (q, J = 8.9, 8.3 Hz, 2H),2.43 (s, 3H), 2.35 (ddd, J = 13.9, 8.5, 5.7 Hz, 1H), 2.10-1.99 (m, 2H),1.85-1.73 (m, 4H), 1.48 (s, 1H), 1.38 (d, J = 2.3 Hz, 9H), 1.06 (dd, J =6.2, 3H), 0.96 (s, 9H). G15

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[4- (II(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methoxy) butyl]phenyl] methoxy)pentan-3- yl]carbamate 879.6(400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.60 (s, 1H), 7.46-7.34 (m, 5H),7.25-7.10 (m, 5H), 6.71-6.56 (m, 2H), 5.15(s, 1H), 4.56 (d, J = 9.5 Hz,1H), 4.49-4.34 (m, 5H), 4.31-4.21 (m, 1H), 3.91 (s, 2H), 3.66 (s, 1H),3.62 (s, 1H), 3.58 (s, 2H), 3.53-3.38 (m, 4H), 2.59 (s, 2H), 2.44 (s,3H), 2.05 (s, 3H), 1.91 (s, 1H), 1.63 (d, J = 7.7 Hz, 2H), 1.56 (s, 2H),1.38 (s, 9H), 1.05 (d, J = 6.1 Hz, 3H), 0.94 (s, 9H). G16

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[4- (II(2S)-1-[(2S,4S)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methoxy) butyl]phenyl] methoxy)pentan-3- yl]carbamate 879.7(400 MHz, DMSO-d₆) δ 8.98 (d, J = 4.4 Hz, 1H), 8.67 (s, 1H), 7.41 (d, J= 11.4 Hz, 1H), 7.40 (s, 3H), 7.35 (d, J = 9.2 Hz, 1H), 7.24-7.19 (m,3H), 7.17-7.11 (m, 3H), 6.67 (s, 1H), 6.59 (d, J = 8.9 Hz, 1H), 5.44 (d,J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42-4.40 (m, 4H), 4.31 (d, J= 5.4 Hz, 1H), 4.25 (d, J = 14.6 Hz, 2H), 3.93-3.84 (m, 3H), 3.31 (s,2H), 2.58 (s, 2H), 2.44 (d, J = 9.7 Hz, 1H), 2.44 (s, 2H), 2.34 (s, 1H),1.76 (d, J = 6.8 Hz, 2H), 1.62 (d, J = 7.5 Hz, 2H), 1.55 (s, 2H), 1.46(s, 1H), 1.38 (d, J = 3.6 Hz, 9H), 1.05 (d, J = 5.8 Hz, 3H), 0.95 (s,9H). G17

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 849.6 (400MHz, CD₃OD) δ 8.89 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 8.3Hz, 2H), 7.45-7.41 (m, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.8Hz, 2H), 6.42 (d, J = 9.5 Hz, 1H), 4.68-4.34 (m, 8H), 3.92 (d, J = 11.0Hz, 1H), 3.82 (dd, J = 11.0, 3.9 Hz, 1H), 3.68-3.46 (m, 3H), 2.63 (s,2H), 2.49 (s, 3H), 2.37-2.21 (m, 6H), 2.10 (ddd, J = 13.2, 9.0, 4.5 Hz,1H), 1.98 (d, J = 15.7 Hz, 2H), 1.66-1.65 (m, 5H), 1.45 (s, 9H),1.21-1.13 (m, 3H), 1.05 (s, 9H). G18

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4S)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 849.6 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.62 (t, J = 6.1 Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.45-7.35 (m, 4H), 7.22 (d, J = 7.9 Hz, 3H), 7.12 (d, J = 7.7Hz, 2H), 6.67 (s, 1H), 6.59 (d, J = 9.0 Hz, 1H), 5.42 (d, J = 7.2 Hz,1H), 4.45 (dd, J = 92, 6.7 Hz, 2H), 4.42 (d, J = 2.9 Hz, 2H), 4.36 (dd,J = 8.6, 6.1 Hz, 1H), 4.31-4.16 (m, 2H), 3.93 (dd, J = 10.0, 5.7 Hz,1H), 3.42 (ddd, J = 15.9, 11.0, 5.8 Hz, 2H), 2.54 (d, J = 7.1 Hz, 2H),2.45 (s, 3H), 2.37-2.24 (m, 1H), 2.10-1.98 (m, 2H), 1.74 (dt, J = 12.4,6.0 Hz, 1H), 1.51(s,4H), 1.49 (d, J = 6.9 Hz, 1H), 1.38 (s,9H), 1.05 (d,J = 6.0Hz, 3H), 0.95 (s, 9H). G19

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4-[3- [2-([[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methoxy) ethoxy]propyl] phenyl)methoxy]pentan-3-yl]carbamate 909.7 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.59 (t, J = 6.0Hz, 1H), 7.41- 7.38 (m, 4H), 7.21 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8Hz, 2H), 6.73- 6.57 (m, 2H), 5.15 (d, J = 3.5 Hz, 1H), 4.58 (d, J = 9.6Hz, 1H), 4.50- 4.34 (m, 5H), 4.26 (dd, J = 15.7, 5.6 Hz, 1H), 3.99 (s,2H), 3.73-3.59 (m, 4H), 3.54 (t, J = 4.2 Hz, 2H), 3.45- 3.36 (m, 4H),2.59 (t, J = 7.7 Hz, 2H), 2.45-2.43 (m, 3H), 2.09-1.97 (m, 2H), 1.92 (s,2H), 1.86-1.74 (m, 3H), 1.39 (s, 9H), 1.06 (d, J = 5.9 Hz, 3H), 0.96 (s,9H). G20

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(3- [2-[2-([[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- l,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methoxy) ethoxy]ethoxy] propyl)phenyl]methoxy] pentan-3-yl]carbamate 953.7 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.60 (t, J = 6.1Hz, 1H), 7.46- 7.37 (m, 4H), 7.26-7.19 (m, 3H), 7.14 (t, J = 9.4 Hz,2H), 6.71-6.55 (m, 2H), 5.15 (d, J = 3.5 Hz, 1H), 4.57 (d, J = 9.6 Hz,1H), 4.48-4.34 (m, 5H), 4.25 (dd, J = 15.9, 5.6 Hz, 1H), 3.98 (s, 2H),3.68 (dd, J = 10.9, 3.9 Hz, 1H), 3.65-3.52 (m, 8H), 3.49 (t, J = 4.8 Hz,3H), 3.42-3.31 (m, 4H), 2.58 (dt, J = 15.3, 7.5 Hz, 2H), 2.44 (s, 3H),2.04 (td, J = 10.0, 9.6, 5.4 Hz, 2H), 1.82-1.71 (m, 3H), 1.47 (d, J =9.7 Hz, 1H), 1.38 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H), 0.95 (s, 9H). G21

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(1- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]-2,5,8,11- tetraoxatetradecan- 14- yl)phenyl]methoxy] pentan-3-yl]carbamate 997.7 (400 MHz, DMSO-d₆) δ 8.98 (d, J = 3.4 Hz, 1H), 8.60(s, 1H), 7.40 (d, J = 3.2 Hz, 5H), 7.25-7.18 (m, 3H), 7.14 (d, J = 7.7Hz, 2H), 6.67 (s, 1H), 6.60 (d, J = 9.1 Hz, 1H), 5.15 (d, J = 3.5 Hz,1H), 4.57 (d, J = 9.4 Hz, 1H), 4.49-4.32 (m, 5H), 4.30-4.20 (m, 1H),3.96 (d, J = 2.9 Hz, 2H), 3.71- 3.41 (m, 9H), 3.41-3.33 (m, 2H), 2.58(t, J = 7.9 Hz, 3H), 2.44 (d, J = 3.2 Hz, 3H), 2.06-2.04 (m, 4H), 1.91(s, 2H), 1.78-7.74 (m, 4H), 1.48 (s, 1H), 1.38 (d, J = 3.1 Hz, 9H), 1.06(d, J = 5.8 Hz, 3H), 0.95 (d, J = 2.9 Hz, 9H). G22

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(3- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]propyl) phenyl]methoxy] pentan-3-yl]carbamate 835.4 (400MHz,CDCl₃) δ 8.93 (s, 1H), 7.42-7.35 (m, 5H), 7.25-7.21 (m, 3H), 7.13(d, J = 7.7 Hz, 2H), 6.30- 6.23 (m, 1H), 5.77-5.46 (m, 1H), 4.73 (q, J =10.0, 7.9 Hz, 2H), 4.64- 4.56 (m, 2H), 4.56-4.47 (m, 2H), 4.34 (d, J =11.5 Hz, 2H), 4.15 (d, J = 11.5 Hz, 1H), 3.65-3.52 (m, 3H), 3.50-3.49(m, 3H), 2.59-2.58 (m, 6H), 2.27-2.11 (m, 4H), 1.93 (s, 2H), 1.60 (d, J= 5.3 Hz, 2H), 1.43 (s, 9H), 1.19 (d, J = 6.2 Hz, 3H), 0.94 (s, 9H). G23

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[2- (II(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]methoxy)ethyl]phenyl]methoxy) pentan-3- yl]carbamate 851.6 (400 MHz, DMSO-d₆) δ8.98 (s, 1H), 8.61 (t, J = 6.0 Hz, 1H), 7.46- 7.36 (m, 4H), 7.35 (d, J =9.5 Hz, 1H), 7.23-7.22 (m, 4H), 6.68 (s, 1H), 6.60 (d, J = 9.1 Hz, 1H),5.16 (d, J = 3.5 Hz, 1H), 4.55 (d, J = 9.6 Hz, 1H), 4.50-4.34 (m, 5H),4.26 (dd, J = 15.9, 5.6 Hz, 1H), 3.97-3.88 (m, 2H), 3.75-3.64 (m, 3H),3.61 (d, J = 10.7 Hz, 1H), 3.45-3.34 (m, 1H), 3.32 (s, 2H), 2.85 (t, J =6.9 Hz, 2H), 2.45-2.43 (m, 3H), 2.08 (s, 1H), 2.08 (d, J = 11.6 Hz, 2H),2.06-1.98 (m, 1H), 1.91 (tt, J = 8.7, 4.4 Hz, 1H), 1.38 (s, 9H), 1.04(d, J = 6.1Hz, 3H), 0.93 (s, 9H). G24

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4-[2- [2-([[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]methyl]carbamoyl) pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2-yl]carbamoyl]methoxy) ethoxy]ethyl] phenyl) methoxy]pentan-3-yl]carbamate 895.7 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.59 (t, J = 6.0Hz, 1H), 7.49- 7.39 (m, 4H), 7.26-7.12 (m, 5H), 6.67 (s, 1H), 6.60 (d, J= 9.1 Hz, 1H), 5.15 (d, J = 3.6 Hz, 1H), 4.59 (d, J = 9.6 Hz, 1H),4.51-4.35 (m, 5H), 4.26 (dd, J = 15.7, 5.6 Hz, 1H), 3.97 (s, 2H),3.70-3.54 (m, 8H), 3.32 (s, 1H), 2.82 (t, J = 7.1 Hz, 2H), 2.44 (s, 3H),2.09 (s, 1H), 2.06 (s, 3H), 1.79 (s, 1H), 1.48 (d, J = 11.5 Hz, 1H),1.39 (s, 9H), 1.06 (d, J = 6.0 Hz, 3H), 0.96 (s, 9H). G25

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(2- [2-[2-([[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methoxy) ethoxy]ethoxy]ethyl) phenyl]methoxy] pentan-3-yl]carbamate 939.7 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.60 (s, 1H),7.47-7.38 (m, 5H), 7.25-7.13 (m, 5H), 6.68 (s, 1H), 6.60 (d, J = 9.0 Hz,1H), 5.15 (d, J = 3.5 Hz, 1H), 4.57 (d, J = 9.5 Hz, 1H), 4.49-4.34 (m,5H), 4.24 (dd, J = 16.0, 5.7 Hz, 1H), 3.97 (s, 2H), 3.72- 3.50 (m, 8H),3.18 (d, J = 5.4 Hz, 2H), 2.76 (t, J = 7.1 Hz, 2H), 2.44 (d, J = 1.7 Hz,3H), 2.04 (s, 3H), 1.91 (s, 3H), 1.79 (s, 1H), 1.46 (s, 1H), 1.38 (s,9H), 1.05 (d, J = 6.1 Hz, 3H), 0.95 (s, 9H). G26

tert-butyl N- [(3.S,4R)-1- carbamoyl-4-[[4-(1- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]-2,5,8,11- tetraoxatridecan-13- yl)phenyl]methoxy] pentan-3- yl]carbamate983.7 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 7.46-7.39 (m, 5H), 7.31-7.16 (m, 5H), 6.72-6.55 (m, 2H), 5.15 (d, J = 3.5 Hz,1H), 4.58 (d, J = 9.5 Hz, 1H), 4.46 (d, J = 8.1 Hz, 1H), 4.43 (d, J =3.5 Hz, 2H), 4.37 (dd, J = 10.8, 4.6 Hz, 2H), 4.25 (dd, J = 15.7, 5.6Hz, 1H), 3.97 (s, 2H), 3.68 (dd, J = 10.7, 4.0 Hz, 1H), 3.64-3.50 (m,14H), 3.46-3.36 (m, 2H), 2.78 (q, J = 6.8 Hz, 2H), 2.45 (s, 3H),2.12-2.01 (m, 3H), 1.79 (dtd, J = 13.7, 7.1, 6.5, 3.4 Hz, 1H), 1.50 (dt,J = 14.1, 8.6 Hz, 1H), 1.39 (s,9H), 1.06 (d, J = 6.0 Hz, 3H), 0.95 (s,9H). G27

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pentyl) phenyl]methoxy] pentan-3-yl]carbamate 863.5 (400MHz, CDCl₃) δ 8.73 (s, 1H), 7.43-7.31 (m, 5H), 7.23 (d, J = 7.8 Hz, 2H),7.14 (d, J = 7.7 Hz, 2H), 6.37 (s, 1H), 6.25 (d, J = 8.7 Hz, 1H), 5.56(s, 1H), 4.88 (d, J = 9.6 Hz, 1H), 4.73 (t, J = 7.9 Hz, 1H), 4.64-4.48(m, 4H), 4.42-4.30 (m, 2H), 4.13 (d, J = 11.3 Hz, 1H), 3.69-3.58 (m,3H), 2.60 (t, J = 7.5 Hz, 2H), 2.54 (s, 3H), 2.27 (t, J = 6.9 Hz, 2H),2.20 (t, J = 7.5 Hz, 2H), 2.16-2.10 (m, 1H), 2.02-1.93 (m, 1H),1.72-1.57 (m, 5H), 1.45 (s, 9H), 1.35-1.20 (m, 2H), 1.21 (d, J = 6.2 Hz,3H), 0.94 (s, 9H). G28

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(6- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]hexyl) phenyl]methoxy]pentan- 3-yl]carbamate 877.6 (400MHz, CD₃OD) δ 8.87 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.3Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 4.63 (s,2H), 4.60-4.42 (m, 5H), 4.35 (d, J = 15.5 Hz, 2H), 3.90 (d, J = 11.0 Hz,1H), 3.80 (dd, J = 11.0, 3.9 Hz, 1H), 3.63-3.46 (m, 2H), 2.59 (t, J =7.6 Hz, 2H), 2.47 (s, 3H), 2.32-2.22 (m, 1H), 2.32-2.11 (m, 4H), 2.08(td, J = 8.9, 4.5 Hz, 1H), 1.95 (d, J = 8.1 Hz, 1H), 1.59 (s, 5H), 1.43(s, 9H), 1.37- 1.32 (m, 6H), 1.17 (dd, J = 13.8, 6. 6 Hz, 3H), 1.03 (s,9H). G29

tert-butyl N- [(3S,4R)-4-[[4-(4- [[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]-1-(methylcarbamoyl)- pentan-3- yl]carbamate 863.7 (400 MHz, CDCl₃) δ 8.72(s, 1H), 7.42-7.30 (m, 5H), 7.23 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8Hz, 2H), 6.35 (s, 1H), 6.16 (d, J = 8.0 Hz, 1H), 4.90 (d, J = 9.5 Hz,1H), 4.71 (t, J = 7.9 Hz, 1H), 4.63-4.55 (m, 1H), 4.58-4.49 (m, 3H),4.40-4.31 (m, 2H), 4.09 (d, J = 11.3 Hz, 1H), 3.60 (m, 3H), 2.79 (d, J =4.6 Hz, 3H), 2.62 (d, J = 6.7 Hz, 2H), 2.53 (s, 3H), 2.28-2.12 (m, 5H),2.00-1.92 (m, 1H), 1.66-1.60 (m, 5H), 1.44 (s, 9H), 1.19 (d, J = 6.1 Hz,3H), 0.94 (s, 9H). G30

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 863.4 (400MHz, CD₃OD) δ 8.89 (s, 1H), 7.52-7.40 (m, 4H), 7.28 (d, J = 8.0 Hz, 2H),7.17 (d, J = 7.9 Hz, 2H), 5.10- 4.97 (m, 1H), 4.66-4.62 (m, 1H),4.62-4.52 (m, 2H), 4.52-4.42 (m, 2H), 3.90 (d, J = 11.1 Hz, 1H), 3.77(dd, J = 11.0, 4.0 Hz, 1H), 3.64-3.46 (m, 2H), 2.65 (d, J = 7.0 Hz, 2H),2.50 (s, 3H), 2.42-2.13 (m, 2H), 1.98 (dtd, J = 13.1, 8.5, 3.6 Hz, 2H),1.70-1.6 1 (m, 6H), 1.53 (d, J = 7.0 Hz, 3H), 1.45 (s, 9H), 1.44-1.42(m, 2H), 1.18 (d, J = 6.2 Hz, 3H), 1.05 (s, 9H). G31

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([1-[4-(4- methyl-1,3-thiazol-5- yl)phenyl]cyclopropyl]carbamoyl)pyrrolidin- 1-yl]-3,3- dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 875.4 (400MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.82 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H),7.37-7.27 (m, 4H), 7.26-7.20 (m, 3H), 7.14 (d, J = 7.9 Hz, 2H), 6.70 (s,1H), 6.62 (d, J = 9.1 Hz, 1H), 5.14 (d, J = 3.5 Hz, 1H), 4.56 (d, J =9.4 Hz, 1H), 4.43 (d, J = 2.3 Hz, 2H), 4.39 (dd, J = 17.1, 9.1 Hz, 2H),3.65 (s, 2H), 3.47-3.36 (m, 2H), 2.56 (d, J = 7.2 Hz, 2H), 2.45 (s, 3H),2.33 (dt, J = 13.9, 6.9 Hz, 1H), 2.15 (dd, J = 14.0, 7.5 Hz, 1H),2.11-2.01 (m, 1H), 2.03-1.95 (m, 1H), 1.94-1.83 (m, 1H), 1.79 (s, 1H),1.60-1.40 (m, 7H), 1.39 (s, 9H), 1.29-1.20 (m, 1H), 1.23-1.10 (m, 2H),1.06 (d, J = 6.0 Hz, 3H), 0.94 (s, 9H). G32

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pent- 1-yn-1- yl)phenyl]methoxy] pentan-3- yl]carbamate859.3 Used directly in next step without further purification G33

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]but-1- yn-1- yl)phenyl]methoxy] pentan-3- yl]carbamate845.4 (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.51-7.40 (m, 4H), 7.37-7.26 (m,4H), 4.73-4.68 (m, 1H), 4.60-4.47 (m, 5H), 4.41-4.33 (m, 1H), 3.92 (d, J= 11.0 Hz, 1H), 3.83 (dd, J = 11.0, 3.9 Hz, 1H), 3.65-3.55 (m, 1H), 3.51(p, J = 6.1 Hz, 1H), 2.80-2.69 (m, 2H), 2.68-2.47 (m, 5H), 2.34-2.18 (m,3H), 2.13-1.92 (m, 2H), 1.67-1.56 (m, 1H), 1.45 (s, 9H), 1.17 (d, J =6.2 Hz, 3H), 1.05 (s, 9H). G34

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[3-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 849.3 (400MHz, CD₃OD) δ 8.90 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.48-7.40 (m, 2H),7.28-7.19 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.17-7.08 (m, 1H),4.69-4.44 (m, 7H), 4.37 (d, J = 15.6 Hz, 1H), 3.93 (d, J = 11.0 Hz, 1H),3.82 (dd, J = 11.0, 3.9 Hz, 1H), 3.59 (s, 1H), 3.50 (p, J = 6.3 Hz, 1H),2.65 (s, 2H), 2.49 (s, 3H), 2.38-2.25 (m, 1H), 2.29-2.16 (m, 2H),2.15-1.97 (m, 1H), 2.01 (s, 1H), 1.70-1.60 (m, 6H), 1.45 (s, 9H), 1.18(d, J = 6.3 Hz, 3H), 1.05 (s, 9H). G35

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[2-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pentyl) phenyl]methoxy] pentan-3-yl]carbamate 863.6 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.88 (d, J = 9.3Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (dd, J= 7.5, 1.5 Hz, 1H), 7.25-7.11 (m, 4H), 6.71 (s, 1H), 6.60 (d, J = 8.8Hz, 1H), 4.57-4.49 (m, 2H), 4.46-4.40 (m, 3H), 4.36 (s, 1H), 4.22 (dd, J= 15.9, 5.5 Hz, 1H), 3.67 (d, J = 4.6 Hz, 2H), 3.40-3.34 (m, 2H), 2.58(t, J = 7.8 Hz, 2H), 2.45 (s, 3H), 2.29 (dt, J = 14.8, 7.6 Hz, 2H),2.15-1.99 (m, 5H), 1.91 (d, J = 4.2 Hz, 1H), 1.82- 1.73 (m, 1H),1.60-1.43 (m, 4H), 1.39 (s, 9H), 1.34-1.28 (m, 2H), 1.08 (d, J = 5.7 Hz,3H), 0.94 (s, 9H). G36

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[6-(2- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]ethyl) naphthalen-2- yl]methoxy]pentan- 3-yl]carbamate871.6 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.82-7.74 (m, 3H), 7.68 (s, 1H),7.48 (m, 3H), 7.47-7.36 (m, 3H), 4.73 (d, J = 11.7 Hz, 1H), 4.67 (d, J =11.8 Hz, 1H), 4.64-4.50 (m, 3H), 4.49 (s, 1H), 4.36 (d, J = 15.5 Hz,1H), 3.90 (d, J = 11.0 Hz, 1H), 3.77 (dd, J = 10.9, 4.0 Hz, 1H),3.64-3.52 (m, 1H), 3.10 (t, J = 7.6 Hz, 2H), 2.81-2.61 (m, 2H), 2.49 (s,3H), 2.36-2.17 (m, 2H), 2.13-1.97 (m, 1H), 1.75-1.58 (m, 2H), 1.42 (s,9H), 1.21 (d, J = 6.1 Hz, 3H), 1.16-1.01 (m, 2H), 0.92 (s, 9H). G37

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl- 1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[6-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]hexanoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 976.2 (400 MHz, CDCl₃) δ 9.68 (s, 1H), 9.25 (s, 1H),8.03-7.79 (m, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.36-7.17 (m, 14H),6.90-6.78 (m, 2H), 6.78-6.60 (m, 1H), 6.53-6.42 (m, 1H), 6.20 (dd, J =8.2, 3.5 Hz, 1H), 5.89-5.73 (m, 2H), 5.31-5.10 (m, 1H), 4.56 (m, 1H),4.46-4.28 (m, 2H), 4.10-3.79 (m, 2H), 3.42 (s, 3H), 3.41-3.27 (m, 1H),3.26-3.09 (m, 1H), 3.07-2.95 (m, 1H), 2.93-2.78 (m, 1H), 2.78-2.56 (m,3H), 2.56-2.35 (m, 1H), 2.34-2.08 (m, 4H), 2.06-1.78 (m, 2H), 1.78-1.53(m, 5H), 1.51-1.40 (m, 9H), 1.40-1.22 (m, 2H). G38

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[7-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]heptanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 990.5 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.80-8.65 (m,1H), 8.18 (t, J = 1.3 Hz, 1H), 7.40-7.14 (m, 10H), 7.04- 6.91 (m, 2H),6.86 (dt, J = 8.1, 1.8 Hz, 1H), 6.73 (d, J = 17.2 Hz, 1H), 6.49 (d, J =6.8 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H),4.38 (m, 2H), 4.19-4.05 (m, 1H), 3.71 (d, J = 14.2 Hz, 1H), 3.5 4-3.34(m, 1H), 3.33 (s, 3H), 3.28-2.98 (m, 2H), 2.90 (ddd, J = 16.8, 12.6, 5.1Hz, 1H), 2.80-2.55 (m, 6H), 2.48- 2.23 (m, 2H), 2.20-2.09 (m, 6H),2.06-1.69 (m, 2H), 1.69-1.46 (m, 5H), 1.43-1.25 (m, 15H). G39

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[8-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]octanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1004.6 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.74 (d, J = 8.5Hz, 1H), 8.19 (t, J = 7.3 Hz, 1H), 7.38-7.19 (m, 11H), 7.05-6.91 (m,2H), 6.85 (dt, J = 8.0, 1.8 Hz, 1H), 6.73 (d, J = 16.8 Hz, 1H), 6.48 (d,J = 6.9 Hz, 1H), 6.09 (d, J = 8.3 Hz, 1H), 5.34 (dd, J = 12.7, 5.3 Hz,1H), 4.48-4.30 (m, 2H), 4.20- 4.05 (m, 1H), 3.80-3.70 (m, 2H), 3.32 (s,3H), 3.25-3.30 (m, 2H), 2.90- 2.80 (m, 1H), 2.75-2.56 (m, 4H), 2.47-2.25(m, 2H), 2.19-1.65 (m, 10H), 1.65-1.45 (m, 8H), 1.37 (s, 9H), 1.36-1.25(m, 4H). G40

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[5-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]pentanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 962.4 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.73 (d, J = 8.5Hz, 1H), 8.18 (dd, J = 18.3, 8.4 Hz, 1H), 7.35-4.10 (m, 12H), 7.03-6.92(m, 2H), 6.89 (d, J = 6.3 Hz, 1H), 6.76-6.70 (m, 1H), 6.46 (d, J = 6.7Hz, 1H), 6.11 (d, J = 8.3 Hz, 1H), 5.37 (dd, J = 12.4, 5.3 Hz, 1H),4.45-4.36 (m, 3H), 4.13 (s, 1H), 3.76 (d, J = 14.7 Hz, 1H), 3.57 (d, J =3.9 Hz, 3H), 3.21 (s, 1H), 3.10 (d, J = 12.7 Hz, 1H), 3.00-2.90 (m, 3H),2.78-2.50 (m, 4H), 2.12 (d, J = 6.6 Hz, 2H), 2.09-2.00 (m, 5H),2.00-1.86 (s, 1H), 1.84-1.75 (m, 2H), 1.70-1.50 (s, 5H), 1.38 (s, 9H).G41

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[8-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]octanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1004.6 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.74 (d, J = 8.7Hz, 1H), 8.18 (d, J = 9.4 Hz, 1H), 7.38-7.20 (m, 11H), 6.99-6.91 (m,2H), 6.86 (dt, J = 5.9, 2.9 Hz, 1H), 6.80-6.70 (m, 1H), 6.47 (d, J = 6.8Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H),4.45-4.30 (m, 3H), 4.19-4.01 (m, 1H), 3.71 (d, J = 13.8 Hz, 2H), 3.55(s, 3H), 3.21 (s, 1H), 3.08 (t, J = 12.6 Hz, 1H), 2.97-2.90 (m, 3H),2.72 (td, J = 13.0, 4.5 Hz, 1H), 2.66- 2.58 (m, 1H), 2.44 (q, J = 7.6Hz, 2H), 2.30-2.20 (m, 1H), 2.15-2.00 (m, 6H), 1.98 (dd, J = 12.2, 5.9Hz, 2H), 1.94-1.90 (m, 1H), 1.85-1.18 (m, 3H), 1.66-1.47 (m, 6H), 1.37(s, 9H), 1.36-1.25 (m, 2H). G42

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[7-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]hept-6-ynoyl]-6- oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 986.8 (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 8.73 (d, J = 8.5Hz, 1H), 8.18 (dd, J = 7.9, 4.9 Hz, 1H), 7.40-7.17 (m, 14H), 7.09 (s,2H), 6.76-6.70 (m, 1H), 6.50 (d, J = 6.6 Hz, 1H), 6.10 (d, J = 8.4 Hz,1H), 5.38 (dd, J = 12.8, 5.3 Hz, 1H), 4.50-4.30 (m, 3H), 4.14 (s, 2H),3.72 (t, J = 12.2 Hz, 2H), 3.34 (s, 3H), 3.23 (d, J = 12.1 Hz, 1H), 3.12(t, J = 12.2 Hz, 1H), 2.96-2.81 (m, 1H), 2.77-2.57 (m, 3H), 2.48- 2.39(m, 3H), 2.22-1.98 (m, 4H), 1.92 (s, 2H), 1.86-1.51 (m, 6H), 1.39 (s,9H). G43

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[8-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]oct-7-ynoyl]-6- oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1000.2 (400 MHz, CDCl₃) δ 10.03 (s, 1H), 9.46 (s, 1H), 7.88(t, J = 7.3 Hz, 1H), 7.71-7.47 (m, 1H), 7.34-7.18 (m, 15H), 7.15-6.97(m, 3H), 6.72 (dd, J = 13.0, 8.1 Hz, 1H), 6.55-6.45 (m, 1H), 6.19 (dd, J= 8.2, 2.5 Hz, 1H), 5.91- 5.71 (m, 2H), 5.21 (d, J = 5.3 Hz, 1H),4.66-4.36 (m, 2H), 4.25-4.13 (m, 1H), 4.09-3.70 (m, 2H), 3.34 (s, 3H),3.20-2.93 (m, 2H), 2.90-2.60 (m, 3H), 2.59-2.33 (m, 4H), 2.33-1.91 (m,6H), 1.91-1.37 (m, 14H). G44

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[8-[2-(2,6-dioxopiperidin-3- yl)-1-oxo-3H- isoindol-4-yl]oct-7- ynoyl]-6-oxo-octahydropyrrolo[1,2- a][1,5]diazocin-5- yl]carbamate 985.7 (400 MHz,CDCl₃) δ 7.92-7.71 (m, 2H), 7.61-7.50 (m, 1H), 7.46 (dt, J = 8.8, 7.4Hz, 1H), 7.39-7.16 (m, 15H), 6.29-6.18 (m, 1H), 5.82-5.67 (m, 1H), 5.59(s, 1H), 5.38-5.15 (m, 1H), 4.90-4.80 (m, 1H), 4.77-4.20 (m, 4H), 4.11(s, 1H), 3.90-3.75 (m, 1H), 3.72-3.03 (m, 2H), 2.94-2.72 (m, 1H),2.60-2.40 (m, 4H), 2.38-1.87 (m, 6H), 1.70-1.47 (m, 12H), 1.45 (s, 9H).. G45

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[7-(2- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]ethyl) naphthalen-2- yl]methoxy]pentan- 3-yl]carbamate871.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.58-8.55 (m, 1H), 8.00 (d, J= 9.4 Hz, 1H), 7.83-7.79 (m, 2H), 7.74 (s, 1H), 7.68 (s, 1H), 7.41 (m, J= 8.3 Hz, 6H), 7.24 (s, 1H), 6.73-6.61 (m, 2H), 5.16 (d, J = 3.5 Hz,1H), 4.69- 4.53 (m, 3H), 4.50-4.34 (m, 3H), 4.23-4.21 (m, 1H), 3.71-3.64(m, 2H), 3.53-3.41 (m, 2H), 3.20-3.07 (m, 1H), 3.02-2.93 (m, 2H),2.72-2.69 (m, 1H), 2.45 (s, 3H) 2.04-1.98 (m, 4H), 1.87-1.65 (m, 1H),1.41-1.39 (m, 1H), 1.38 (s, 9H), 1.10 (d, J = 5.9 Hz, 3H), 0.89 (s, 9H)G46

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[6-(3- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]propyl) naphthalen-2- yl]methoxy]pentan- 3-yl]carbamate885.40 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.90-7.73 (m, 4H), 7.66 (s, 1H),7.52- 7.34 (m, 5H), 4.78-4.50 (m, 5H), 4.37 (d, J = 15.5 Hz, 1H), 3.95(d, J = 11.0 Hz, 1H), 3.83 (dd, J = 11.0, 3.9 Hz, 1H), 3.68-3.47 (m,3H), 2.90-2.77 (m, 2H), 2.49 (s, 3H), 2.42-2.19 (m, 4H), 2.16-1.98 (m,4H), 1.66 (s, 1H), 1.41 (s, 7H), 1.40 (d, J = 1.7 Hz, 2H), 1.22 (dd, J =6.1, 3.1 Hz, 4H), 1.06 (s, 9H) G47

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[5-(2- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]ethyl) naphthalen-2- yl]methoxy]pentan- 3-yl]carbamate871.35 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H), 8.06(d, J = 9.1 Hz, 2H), 7.87-7.82 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.56-7.49 (m, 1H), 7.43-7.38 (m, 6H), 7.24 (s, 1H), 6.71 (s, 1H), 6.66 (d, J= 8.9 Hz, 1H), 5.17 (d, J = 3.5 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H),4.67- 4.56 (m, 2H), 4.49-4.35 (m, 3H), 4.22 (dd, J = 15.7, 5.3Hz, 1H),3.71- 3.67 (m, 2H), 3.50-3.44 (m, 3H), 3.28-3.24 (m, 1H), 2.61-2.53 (m,1H), 2.45 (s, 3H), 2.05 (t, J = 10.6 Hz, 3H), 1.90-1.80 (m, 4H), 1.50(s, 1H), 1.37 (s, 9H), 1.11 (d, J = 5.8 Hz, 3H), 0.93 (s, 9H). G48

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[5-(3- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]propyl) naphthalen-2- yl]methoxy]pentan- 3-yl]carbamate885.40 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.06(d, J = 8.8 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.51 (dd, J = 8.8, 1.7 Hz, 1H), 7.44-.40 (m, 3H),7.40-7.37 (m, 2H), 7.32 (d, J = 7.0 Hz, 1H), 7.23 (s, 1H), 6.72-6.61 (m,2H), 5.13 (d, J = 3.6 Hz, 1H), 4.68-4.58 (m, 3H), 4.45-4.42 (m, 2H),4.37 (s, 1H), 4.24-4.20 (m, 1H), 3.69 (s, 2H), 3.53-3.42 (m, 2H),3.02-2.97 (m, 2H), 2.45 (s, 3H), 2.39 (q, J = 7.2 Hz, 1H), 2.28-2.25 (m,1H), 2.10- 2.01 (m, 3H), 1.95-1.80 (m, 4H), 1.56-1.46 (m, 1H), 1.37 (s,9H), 1.11 (d, J = 5.9 Hz, 3H), 0.96 (s, 9H). G49

tert-butyl N- [(3.S,4R)-1- carbamoyl-4-([4- [(1E)-5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pent- 1-en-1- yl]phenyl]methoxy) pentan-3- yl]carbamate861.40 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 2H), 7.92(d, J = 9.3 Hz, 1H), 7.44-7.34 (m, 9H), 7.28- 7.20 (m, 3H), 6.69 (s,1H), 6.61 (d, J = 9.1 Hz, 1H), 6.38 (d, J = 15.9 Hz, 1H), 6.33-6.22 (m,1H), 5.76 (s, 2H), 5.13 (t, J = 3.6 Hz, 1H), 4.62- 4.51 (m, 2H),4.47-4.41 (m, 4H), 4.36 (s, 1H), 4.25-4.19 (m, 2H), 3.48-3.36 (m, 1H),2.45 (s, 3H), 2.38-2.26 (m, 1H), 2.23-2.13 (m, 2H), 2.08-2.02 (m, 2H),1.97-1.85 (m, 1H), 1.71- 1.61 (m, 1H), 1.38 (s, 9H), 1.08-1.04 (d, J =6.0 Hz, 3H), 0.95 (s, 9H) G50

tert-butyl N- [3S,4R)-1- carbamoyl-4-([4- [(1E)-4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- l,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]but-1- en-1- yl]phenyl]methoxy) pentan-3- yl]carbamate847.35 (400 MHz, CDCl₃) δ 8.68 (s, 1H), 7.38- 7.34 (m, 5H), 7.30 (d, J =8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.41 (d, J = 15.5 Hz, 1H), 6.34(s, 1H), 6.21- 6.10 (m, 2H), 5.39-5.33 (m, 1H), 5.30 (s, 1H), 4.84 (d, J= 9.6 Hz, 1H), 4.71-4.45 (m, 6H), 4.38-4.28 (m, 2H), 4.08 (d, J = 11.4Hz, 1H), 3.68- 3.52 (m, 3H), 2.54-2.52 (m, 3H), 2.38 (t, J = 7.6 Hz,2H), 2.23 (t, J = 7.0 Hz, 2H), 2.12-2.03 (m, 1H), 2.00-1.90 (m, 1H),1.63-1.58 (m, 2H ) 1.42 (s, 9H), 1.25 (s, 1H), 1.18 (d, J = 6.2 Hz, 3H),0.91 (s, 9H) G51

tert-butyl N- [3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]piperidin-1- yl)phenyl]methoxy] pentan-3- yl]carbamate877.13 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 7.87(d, J = 9.2 Hz, 1H), 7.48-7.37 (m, 4H), 7.2 1 (s, 1H), 7.15 (d, J = 8.5Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 6.57 (d, J = 9.0 Hz,1H), 5.14(s, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.50-4.40 (m, 1H), 4.40-4.30(m, 3H), 4.23 (dd, J = 15.8, 5.5 Hz, 1H), 3.73-3.63 (m, 5H), 2.71-2.59(m, 2H), 2.45 (s, 3H), 2.11-1.95 (m, 4H), 1.95-1.86 (m, 1H), 1.86-1.73(m, 2H), 1.73-1.57 (m, 3H), 1.39 (s, 9H), 1.29-1.22 (m, 3H), 1.04 (d, J= 5.9 Hz, 3H), 0.95 (s, 9H) G52

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[4- ([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methyl) piperidin-1- yl]phenyl]methoxy) pentan-3-yl]carbamate 890.51 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.49 (d, J = 8.3Hz, 2H), 7.46-7.41 (m, 2H), 7.26-7.21 (m, 2H), 6.98-6.92 (m, 2H),4.69-4.65 (m, 1H), 4.61- 4.56 (m, 2H), 4.54-4.50 (m, 2H), 4.49- 4.35 (m,3H), 3.95 (d, J = 11.0 Hz, 1H), 3.83 (dd, J = 11.0,3.9Hz, 1H), 3.67 (dd,J = 12.1, 3.4 Hz, 2H), 3.60- 3.47 (m, 2H), 2.74-2.65 (m, 2H),2.29-2.21(m, 5H), 2.14-2.08 (m, 1H), 2.01-1.88 (m, 2H), 1.84-1.77 (m,2H), 1.62-1.54 (m, 1H), 1.50-1.42 (m, 13H), 1.16 (d, J = 6.1Hz, 3H),1.07 (s, 9H) G53

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[4- (2-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]ethyl) piperidin-1- yl]phenyl]methoxy) pentan-3-yl]carbamate 904.65 (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.89 (d, J = 9.0Hz, 1H), 7.53-7.40 (m, 5H), 7.24 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0Hz, 2H), 6.39 (d, J = 9.6 Hz, 1H), 4.71-4.64 (m, 1H), 4.58 (t, J = 8.3Hz, 2H), 4.56-4.47 (m, 3H), 4.47-4.34 (m, 3H), 3.93 (d, J = 11.0 Hz,1H), 3.83 (dd, J = 11.0, 3.9 Hz, 1H), 3.67 (d, J = 12.8 Hz, 2H), 3.61-3.44 (m, 3H), 2.66 (t, J = 10.6, 2H), 2.50 (s, 3H), 2.46-2.31 (m, 2H),2.29- 2.17 (m, 3H), 2.13-2.06 (m, 1H), 2.05-1.92 (m, 1H), 1.84 (d, J =11.8 Hz, 2H), 1.67-1.53 (m, 3H), 1.45 (s, 9H), 1.42-1.26 (m, 3H), 1.16(d, J = 6.2 Hz, 3H), 1.06 (s, 9H) G54

9H-fluoren-9- ylmethyl(1R,2S,5S)- 2-[[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-3- azabicyclo[3.1.0] hexane-3-carboxylate 1080.20 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.90 (t, J = 7.4Hz, 4H), 7.65 (t, J = 7.3 Hz, 3H), 7.49-7.27 (m, 8H), 7.22 (d, J = 6.3Hz, 2H), 7.12 (d, J = 7.4 Hz, 2H), 6.64 (d, J = 21.2 Hz, 1H), 5.15-5.13(m, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.51-4.41 (m, 3H), 4.40-4.34 (m, 1H),4.27-4.21 (m, 2H), 4.16-4.12 (m, 2H), 3.70-3.65 (m, 2H), 3.49-3.43 (m,2H), 3.36-3.28 (m, 3H), 3.25-3.18 (m, 6H), 2.45 (s, 3H), 2.36-2.25 (m,1H), 2.19-1.96 (m, 2H), 1.91-1.79 (m, 2H), 1.62-1.49 (m,5H), 1.20-1.09(m, 4H), 0.94 (s, 9H), 0.70-0.69 (m, 1H), 0.57-0.52 (m, 1H) G55

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[7-[3-(2,6-dioxopiperidin-3- yl)-1-methyl-2-oxo- 1,3-benzodiazol-5-yl]heptanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 990.40 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.75 (dd, J =8.3, 2.6 Hz, 1H), 8.20- 8.14 (m, 1H), 7.41-7.20 (m, 11H), 7.06 (d, J =7.9 Hz, 1H), 7.02-6.87 (m, 2H), 6.78-6.72 (m, 1H), 6.50 (d, J = 6.8 Hz,1H), 6.10 (d, J = 8.4 Hz, 1H), 5.36 (dd, J = 12.8, 5.4 Hz, 1H),4.46-4.25 (m, 3H), 4.19-4.05 (m, 1H), 3.75-3.70 (m, 1H), 3.60-3.42 (m,2H), 3.30-3.19 (m, 1H), 3.09 (t, J = 12.7 Hz, 1H), 2.97-2.84 (m, 1H),2.80-2.73 (m, 1H), 2.71-2.62 (m, 1H), 2.62-2.53 (m, 3H), 2.48-2.26 (m,2H), 2.21-2.06 (m, 3H), 2.05-1.86 (m, 4H), 1.85-1.68 (m, 3H), 1.64- 1.57(m, 6H), 1.38 (s, 9H), 1.36-1.30 (m, 4H) G56

tert-butyl N-[(2S)-4- carbamoyl-1-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]butan- 2-yl]carbamate 849.35 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 9.3Hz, 1H), 7.47-7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.26-7.22 (d, J =8.0 Hz, 4H), 7.15 (d, J = 8.1 Hz, 3H), 5.11 (d, J = 3.5 Hz, 1H), 4.92(p, J = 7.4 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (d, J = 3.4 Hz, 4H),4.28 (s, 1H), 3.68-3.51 (m, 2H), 3.32- 3.28 (m, 4H), 2.56 (d, J = 7.0Hz, 1H), 2.46 (s, 4H), 2.36-2.24 (m, 2H), 2.18-2.10 (m, 1H), 2.08-1.96(m, 2H), 1.85-1.67 (m, 1H), 1.59-1.43 (m, 7H), 1.38 (s, 9H), 0.94 (s,9H) G57

tert-butyl N-[[4-(3- [[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl] carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]propyl) phenyl]methyl]carbamate 706.40 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz,1H), 7.91 (d, J = 9.2 Hz, 1H), 7.46-7.30 (m, 5H), 7.15-7.12 (m, 4H),5.15-5.13 (m, 1H), 4.56 (d, J = 9.3 Hz, 1H), 4.45-4.43 (m, 2H), 4.35 (d,J = 4.2 Hz, 1H), 4.22 (dd, J = 15.9, 5.4 Hz, 1H), 4.08 (d, J = 6.2 Hz,2H), 3.67 (d, J = 3.5 Hz, 2H), 3.32-3.30 (m, 2H), 2.45 (s, 3H), 2.27(dt, J = 14.8, 7.6 Hz, 1H), 2.18-2.14 (m, 1H), 2.05-2.03 (m, 1H), 1.92-1.90 (m, 1H), 1.79-1.75 (m, 2H), 1.39 (s, 9H), 0.95 (s, 9H) G58

tert-butyl N-1(1S)-3- carbamoyl-1-([[4-(3- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]propyl) phenyl]methyl] carbamoyl)propyl] carbamate 834.30(400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.23 (t, J= 5.9 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.40 (d, J = 8.4 Hz, 4H), 7.26(s, 1H), 7.17-7.08 (m, 4H), 6.90 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 5.12(d, J = 3.5 Hz, 1H), 4.56 (d, J = 9.4 Hz, 1H), 4.47-4.40 (m, 2H), 4.35(d, J = 4.2 Hz, 1H), 4.26-4.22 (m, 2H), 3.88 (t, J = 7.0 Hz, 1H),3.67-3.65 (m, 2H), 2.45 (s, 3H), 2.35-2.20 (m, 1H), 2.19-1.99 (m, 4H),1.94-1.67 (m, 5H), 1.38 (s, 9H), 1.04 (d, J = 6.1 Hz, 3H), 0.94 (s, 9H)G59

tert-butyl N-[[4-(4- [[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl] carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methyl]carbamate 720.30 (400 MHz, DMSO-d₆) 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz,1H), 7.88 (d, J = 9.3 Hz, 1H), 7.41 (q, J = 8.3 Hz, 4H), 7.33 (t, J =6.2 Hz, 1H), 7.12(s, 4H), 5.13 (d, J = 3.6 Hz, 1H), 4.55 (d, J = 9.3 Hz,1H), 4.49-4.38 (m, 2H), 4.35 (s, 1H), 4.22 (dd, J = 15.9, 5.4 Hz, 1H),4.08 (d, J = 6.2 Hz, 2H), 3.72-3.60 (m, 2H), 2.54 (s, 2H), 2.45 (s, 3H),2.30 (q, J = 6.8 Hz, 1H), 2.18-2.10 (m, 1H), 2.03 (t, J = 10.2 Hz, 1H),1.90-1.80 (m, 1H), 1.52- 1.48 (m, 4H), 1.39 (s, 9H), 0.94 (s, 9H) G60

tert-butyl N-1(1S)-3- carbamoyl-1-([[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methyl] carbamoyl)propyl] carbamate 848.30(400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.51-7.42 (m, 4H), 7.21 (d, J = 7.7 Hz,2H), 7.16 (s, 2H), 4.67-4.49 (m, 6H), 4.42-4.34 (m, 2H), 4.07 (s, 1H),3.92 (d, J = 11.0 Hz, 1H), 3.82 (dd, J = 11.0, 3.9 Hz, 1H), 3.56-3.47(m, 1H), 3.50 (d, J = 1.6 Hz, 1H), 3.17- 3.13 (m, 1H), 2.65-2.58 (m,3H), 2.49 (s, 3H), 2.36-2.21 (m, 4H), 2.14-1.98 (m, 2H), 1.94-1.81 (m,2H), 1.45 (s, 9H), 1.05 (s, 9H) G61

tert-butyl N-[[4-(5- [[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl] carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pentyl) phenyl]methyl]carbamate 734.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz,1H), 7.85 (d, J = 9.3 Hz, 1H), 7.41 (q, J = 8.2 Hz, 4H), 7.32 (d, J =6.3 Hz, 1H), 7.12 (s, 4H), 5.13 (d, J = 3.5 Hz, 1H), 4.54 (d, J = 9.4Hz, 1H), 4.47-4.37 (m, 2H), 4.22 (dd, J = 15.9, 5.5 Hz, 1H), 4.08 (d, J= 6.2 Hz, 2H), 3.73-3.60 (m, 2H), 3.52-3.40 (m, 1H), 2.45 (s, 3H), 2.26(dt, J = 14.8, 7.5 Hz, 1H), 2.08 (ddd, J = 32.5, 17.3, 7.8 Hz, 2H),1.97-1.83 (m, 1H), 1.63-1.44 (m, 4H), 1.39 (s, 9H), 1.28-1.24 (m, 2H),0.93 (s, 9H) G62

tert-butyl N-1(1S)-3- carbamoyl-1-([[4-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pentyl) phenyl]methyl] carbamoyl)propyl] carbamate 862.40(400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.23 (t, J= 5.8 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.40 (q, J = 8.2 Hz, 4H), 7.26(s, 1H), 7.15-7.08 (m, 4H), 6.90 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 5.13(d, J = 3.5 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.43 (q, J = 7.4 Hz, 2H),4.35 (d, J = 4.1 Hz, 2H), 4.22 (dt, J = 11.0, 5.4 Hz, 3H), 3.90-3.87 (m,1H), 3.82-3.73 (m, 1H), 3.68-3.64 (m, 2H), 2.45 (s, 3H), 2.26-2.22 (m,1H), 2.15-1.98 (m, 4H), 1.94-1.78 (m, 2H), 1.73-1.69 (m, 1H), 1.52-1.47(m, 4H), 1.38 (s, 9H), 1.32-1.21 (m, 3H), 0.93 (s, 9H). G63

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[3-(2-[2-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]ethyl]phenyl) propanoyl]- 6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1038.40 (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 8.70 (d, J = 8.3 Hz, 1H), 8.21- 8.12 (m, 1H), 7.30-7.2.5 (m, 14H),7.12-7.10 (m, 3H), 7.01 (t, J = 7.8 Hz, 1H), 6.95-6.91 (m, 1H), 6.74 (t,J = 22.0 Hz, 1H), 6.09 (d, J = 8.2 Hz, 1H), 5.39-5.29 (m, 1H), 4.37-4.34 (m, 3H), 3.95-3.92 (m, 1H), 3.74-3.71 (m, 1H), 3.35-3.31 (m, 5H),3.14-3.05 (m, 1H), 3.01-2.58 (m, 11H), 2.16-1.52 (m, 11H), 1.37 (s, 9H).G64

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[3-[(1r,4r)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] propanoyl]-octahydropyrrolo[1,2-a] [1,5]diazocin-5- yl]carbamate 1030.45 (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.17 (t, J = 8.8 Hz,1H), 7.39-7.18 (m, 11H), 7.02-6.96 (m, 2H), 6.81 (dd, J = 8.1, 1.7 Hz,1H), 6.72 (d, J = 19.1 Hz, 1H), 6.47 (d, J = 6.9 Hz, 1H), 6.09 (d, J =8.3 Hz, 1H), 5.76 (s, 2H), 5.34 (dd, J = 12.6, 5.4 Hz, 1H), 4.43-4.27(m, 2H), 4.09-4.01 (m, 1H), 3.70- 3.66 (m, 2H), 3.32-3.30 (m, 11H),3.24- 3.04 (m, 1H), 2.98-2.84 (m, 1H), 2.75-2.60 (m, 2H), 2.47-2.44 (m,1H), 2.17-2.04 (m, 3H), 2.09-1.90 (m, 2H), 1.83-1.56 (m, 6H), 1.43-1.34(m, 11H), 1.18 (t, J = 7.1 Hz, 1H), 0.98- 0.79 (m, 4H) G65

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[3′- ([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methyl)- [1,1′-biphenyl]-4- yl]methoxy]pentan-3-yl]carbamate 883.43 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.58 (t, J =6.0 Hz, 1H), 8.18 (d, J = 9.3 Hz, 1H), 7.62-7.57 (m, 3H), 7.50 (dd, J =7.9, 1.6 Hz, 1H), 7.40-7.33 (m, J = 9.7, 6.5 Hz, 7H), 7.29-7.21 (m, 2H),6.72-6.61 (m, 2H), 5.76 (s, 2H), 5.12 (d, J = 3.5 Hz, 1H), 4.58- 4.50(m, 3H), 4.48-4.41 (m, 2H), 4.35 (s, 1H), 4.23 (dd, J = 15.8, 5.4 Hz,1H), 3.75 (d, J = 13.8 Hz, 1H), 3.70-3.61 (m, 2H), 3.52 (d, J = 13.7 Hz,1H), 3.47-3.42 (m, 1H), 2.45 (s, 3H), 2.07 (q, J = 9.3, 8.8 Hz, 2H),1.91 (ddd, J = 12.9, 8.5, 4.5 Hz, 1H), 1.81 (d, J = 9.9 Hz, 1H),1.54-1.50 (m, 1H), 1.39 (s, 9H), 1.09 (d, J = 6.0 Hz, 3H), 0.93 (s, 9H)G66

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 867.09 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3 Hz,1H), 7.50-7.41 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.27 (s, 1H),7.05-6.93 (m, 2H), 6.87-6.77 (m, 2H), 6.74 (s, 1H), 5.10 (d, J = 3.5 Hz,1H), 4.98-4.86 (m, 2H), 4.51 (d, J = 9.3 Hz, 1H), 4.45-4.41 (m, 1H),4.28 (s, 1H), 3.91 (d, J = 6.1 Hz, 2H), 3.77- 3.70 (m, 1H), 3.61 (d, J =3.8 Hz, 2H), 2.58-2.54 (m, 2H), 2.46 (s, 3H), 2.27-2.23 (m, 1H), 2.12(s, 1H), 2.11-2.09 (m, 3H), 2.06-1.96 (m, 1H), 1.81-1.77 (m, 1H),1.55-1.52 (m, 4H), 1.51-1.47 (m, 1H), 1.39 (s, 9H), 1.39-1.35 (m, 2H),1.32-1.28 (m, 2H), 1.27-1.23 (m, 1H), 0.93 (s, 9H) G67

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4-[[3- ([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methyl) cyclobutyl]methyl] phenyl)methoxy]pentan-3-yl]carbamate 875.30 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.65 (t, J = 6.0Hz, 1H), 7.74 (dd, J = 18.4, 9.1 Hz, 1H), 7.51-7.40 (m, 4H), 7.31-7.08(m, 4H), 6.41 (d, J = 9.5 Hz, 1H), 4.64 (d, J = 9.1 Hz, 1H), 4.62-4.42(m, 7H), 4.43-4.33 (m, 1H), 3.90 (d, J = 11.1 Hz, 1H), 3.85-3.77 (m,1H), 3.66-3.56 (m, 2H), 3.50 (q, J = 6.1 Hz, 1H), 2.75 (d, J = 7.7 Hz,1H), 2.69-2.56 (m, 2H), 2.49 (d, J = 1.1 Hz, 3H), 2.49-2.32 (m, 2H),2.31-2.16 (m, 4H), 2.15-2.03 (m, 1H), 2.03-1.81 (m, 2H), 1.66-1.58 (m,1H), 1.54-1.47 (m, 1H), 1.45 (s, 9H), 1.17 (s, 3H), 1.04 (s, 9H) G68

tert-butyl N- [(3S,4R)-1- carbamoyl-4-([4-[3- ([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methyl) cyclobutyl]phenyl] methoxy)pentan-3- yl]carbamate861.70 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 2H),7.43 (dd, J = 8.2, 1.6 Hz, 2H), 7.29 (dd, J = 8.1, 6.1 Hz, 2H),7.23-7.19 (m, 2H), 4.66 (d, J = 4.2 Hz, 1H), 4.64- 4.44 (m, 7H), 4.38(dd, J = 15.5, 1.8 Hz, 1H), 3.92 (dd, J = 11.3, 1.9 Hz, 1H), 3.82 (dd, J= 11.0, 3.9 Hz, 1H), 3.71-3.47 (m, 2H), 3.42-3.35 (m, 1H), 2.79-2.50 (m,2H), 2.49 (d, J = 1.0 Hz, 3H), 2.48-2.36 (m, 1H), 2.39-2.15 (m, 3H),2.15-2.04 (m, 1H), 2.04-1.93 (m, 1H), 1.88-1.84 (m, 1H), 1.66-1.59 (m,1H), 1.57 (s, 1H), 1.45 (s, 9H), 1.17 (s, 3H), 1.06 (s, 9H). G69

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[2-(4-[[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]methyl]piperazin- 1-yl)acetyl]-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1018.43 (400 MHz, DMSO-d₆) δ 12.70 (s,1H), 11.12 (s, 1H), 9.53-9.38 (m, 1H), 8.81 (dd, J = 11.2, 8.2 Hz, 1H),8.71- 8.59 (m,1H), 8.28-8.21 (m, 1H), 7.43- 7.19 (m, 10H), 7.19-6.90 (m,2H), 6.79 (d, J = 12.3 Hz, 1H), 6.12-6.07 (m, 1H), 5.39 (s, 1H),4.42-4.27 (m, 3H), 3.09-2.97 (m, 32H), 2.20-2.06 (m, 2H), 1.40 (s, 9H)G70

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[2-(4-[[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]methyl]piperidin- 1-yl)acetyl]-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1017.45 (400 MHz, DMSO-d₆) δ 11.09 (s,1H), 8.62-8.55 (m, 1H), 8.31-8.20 (m, 1H), 7.44-7.16 (m, 11H), 7.10-6.97(m, 2H), 6.91-6.53 (m, 3H), 6.09 (d, J = 8.2 Hz, 1H), 5.35 (dd, J =12.8, 5.4 Hz, 1H), 4.62 (d, J = 51.5 Hz, 2H), 4.47-4.11 (m, 7H),3.95-3.54 (m, 4H), 3.31 (s, 3H), 2.96-2.86 (m, 2H), 2.76-2.57 (m, 4H),2.38-2.32 (m, 2H), 2.21-2.01 (m, 4H), 2.06-1.83 (m, 3H), 1.69-1.50 (m,2H), 1.48-1.44 (m, 4H), 1.38 (s, 9H), 1.28-1.22 (m, 1H) G71

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(4-[4-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]piperidin-1- yl]butanoyl)-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1031.45 ¹H NMR (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.38-7.19(m, 11H), 7.11-6.86 (m, 3H), 6.81- 6.66 (m, 1H), 6.58 (d, J = 6.8 Hz,1H), 6.09 (dd, J = 8.4, 2.4 Hz, 1H), 5.34 (dd, J = 12.8, 5.4 Hz, 1H),4.60-4.08 (m, 6H), 3.78 (dt, J = 12.1, 6.1 Hz, 2H), 3.33 (s, 3H),3.24-2.85 (m, 4H), 2.79-2.54 (m, 2H), 2.49-2.30 (m, 2H), 2.22-1.84 (m,6H), 1.84-1.58 (m, 11H), 1.38 (s, 9H), 1.28-1.20 (m, 3H), 0.92-0.82 (m,1H) G72

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(3-[4-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]piperidin-1- yl]propanoyl)-6- oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1017.45 (400 MHz, DMSO-d₆) δ 11.12 (s,1H), 8.66 (d, J = 8.4 Hz, 1H), 8.36-8.19 (m, 1H), 7.39-7.20 (m, 11H),7.14- 7.00 (m, 2H), 6.92 (d, J = 7.9 Hz, 1H), 6.82 (s, 1H), 6.71 (d, J =21.6 Hz, 1H), 6.16-6.04 (m, 1H), 5.36 (dt, J = 13.0, 6.4 Hz, 1H),4.70-4.25 (m, 2H), 3.75-3.50 (m, 8H), 3.35 (s, 3H), 3.26-3.14 (m, 1H),2.95-2.81 (m, 2H), 2.81-2.55 (m, 2H), 2.15 (t, J = 8.2 Hz, 4H),2.07-1.87 (m, 8H), 1.48- 1.42 (m, 8H), 1.38 (s, 9H) G73

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[(4-[[1- ([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]methyl) piperidin-4- yl]methyl]phenyl) methoxy]pentan-3-yl]carbamate 904.75 (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.93 (d, J = 8.4Hz,1H), 7.56(s, 1H), 7.49 (t, J = 6.0 Hz, 1H), 7.43-7.34 (m, 4H), 7.24 (d,J = 7.8 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.40 (s, 1H), 5.32 (m, 1H),4.90 (d, J = 9.7 Hz, 1H), 4.77 (t, J = 8.0 Hz, 1H), 4.66- 4.49 (m, 3H),4.45-4.30 (m, 3H), 4.22-4.13 (m, 1H), 3.72-3.58 (m, 3H), 3.04-2.88 (m,2H), 2.87-2.74 (m, 2H), 2.54 (s, 3H), 2.33-2.23 (m, 2H), 2.22-2.04 (m,4H), 2.03-1.87 (m, 2H), 1.7-1.62 (m, 4H), 1.54 (td, J = 7.3, 3.7 Hz,1H), 1.45 (s, 9H), 1.39-1.25 (m, 3H), 1.21 (d, J = 6.3 Hz, 3H), 0.98 (s,9H) G74

Tert-butyl N-[(2S)-4- carbamoyl-1-[4-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 835.35 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.84 (d, J = 9.3 Hz,1H), 7.41 (q, J = 8.2 Hz, 4H), 7.26 (s, 1H), 7.11-7.05 (m, 2H),6.86-6.77 (m, 3H), 6.72 (s,1H), 5.1 (d, J = 3.6 Hz, 1H), 4.59-4.32 (m,4H), 4.25-4.18 (m, 1H), 3.88-3.75 (m, 2H), 3.75-3.62 (m, 2H), 3.32-3.28(m, 2H), 2.47 (d, J = 6.8 Hz, 3H), 2.45 (s, 3H), 2.32-2.00 (m, 4H),1.96- 1.76 (m, 2H), 1.54 (m, 4H), 1.39 (s, 9H), 1.24 (p, J = 7.6 Hz,2H), 0.93 (s, 9H) G75

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 835.44 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.84 (d, J = 9.3 Hz,1H), 7.46-7.35 (m, 4H), 7.25 (s, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.81 (d,J = 8.5 Hz, 1H), 6.77-6. 73 (m, 3H), 4.54 (d, J = 9.4 Hz, 1H), 4.49-4.39(m, 2H), 4.36 (s, 1H), 4.22 (dd, J = 15.9, 5.5 Hz, 1H), 3.90-3.77 (m,1H), 3.72-3.61 (m, 2H), 3.05- 3.00 (m, 5H), 2.45 (s, 3H), 2.31-2.23 (m,1H), 2.17-2.09 (m, 2H), 2.02 (d, J = 9.5 Hz, 1H), 1.94-1.87 (m, 1H),1.76-1.72 (m, 4H), 1.59-1.44 (m, 4H), 1.39 (s, 9H), 1.30-1.23 (m, 2H),0.93 (s, 9H) G76

tert-butyl N-[(2S)-4- carbamoyl-1-[3-[4- (2-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]ethyl) phenyl]propoxy]butan- 2-yl]carbamate 835.07 (400MHz, DMSO-d₆) δ 8.99 (s, 1 H), 8.55 (t, J = 6.1 Hz, 1H), 7.96-7.87 (m,1H), 7.41 (q, J = 8.3 Hz, 5H), 7.22 (d, J = 7.6 Hz, 2H), 7.15-7.05 (m,4H), 6.69 (s, 1H), 6.62-6.51 (m, 1H), 5.74 (d, J = 14.1 Hz, 1H), 5.13(s, 1H), 4.60-4.34 (m, 5H), 3.67 (s, 2 H), 2.84-2.74 (m, 3H), 2.57 (d, J= 7.3 Hz, 2H), 2.45 (s, 3H), 2.06 (d, J = 8.7 Hz, 4H), 1.94-1.87 (m,2H), 1. 77-1.68 (m, 3H), 1.37 (s, 9H), 1.32- 1.28 (m, 2H), 0.90 (s, 9H)G77

tert-butyl N-[(2S)- 4-carbamoyl-1-([[4- (4-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methyl](methyl) amino)butan-2- yl]carbamate848.60 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.51-7.41 (m, 4H), 7.24 (d, J =7.9 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 4.65 (s, 1H), 4.62-4.55 (m, 2H),4.54-4.50 (m, 2H), 4.37 (d, J = 15.6 Hz, 1H), 3.92 (d, J = 11.0 Hz, 1H),3.82 (dd, J = 10.9, 3.9 Hz, 1H), 3.74 (s, 1H), 3.55-3.47 (m, 2H), 2.63(t, J = 8.0 Hz, 2H), 2.49 (s, 3H), 2.45-2.16 (m, 10H), 2.13-2.07 (m,1H), 1.99-1.87 (m, 1H), 1.70-1.63 (m, 4H), 1.47 (s, 9H), 1.05 (s, 9H)G78

9-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidin-1-yl)- 3,3-dimethyl-1- oxobutan-2-yl)amino)-9- oxononanoic acid 601.45 (400 MHz, DMSO-d₆) δ 11.88 (s, 1H),8.99 (s, 1H), 8.56 (t, J = 5.9 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.41(q, J = 8.4 Hz, 4H), 5.12 (d, J = 3.6 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H),4.46- 4.42 (m, 2H), 4.35 (s, 1H), 4.22 (dd, J = 16.0, 5.5 Hz, 1H), 3.66(s, 1H), 2.45 (s, 3H), 2.32-2.05 (m, 4H), 2.05- 2.01 (m, 1H), 1.96-1.85(m, 1H), 1.50-1.46 (m, 1H), 1.27-1.23 (m, 8H), 0.94 (s, 9H) G79

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl- 1-(diphenylmethylcarb- amoyl)propyl]carba- moyl]-3-(8-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- l,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]oct- anoyl)-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1203.51 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.72 (d, J = 8.6Hz, 1H), 8.56 (t, J = 6.2 Hz, 1H), 8.18 (t, J = 7.4Hz, 1 H), 7.83 (d, J= 9.5 Hz, 1H), 7.41 (q, J = 8.2 Hz, 4H), 7.35-7.24 (m, 10H), 7.22 (s,1H), 6.72 (d, J = 17.5 Hz, 1H), 6.47 (d, J = 7.0 Hz, 1H), 6.10 (d, J =8.4Hz, 1H), 5.12 (d, J = 3.6 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.49-4.28 (m, 5H), 4.22 (dd, J = 15.9, 5.5 Hz, 1H), 4.11 (s, 1H), 3.74-3.64(m, 3H), 3.46 (s, 1H), 3.26-3.16 (m, 1H), 3.08 (s, 1H), 2.45 (s, 3H),2.28- 2.24 (m, 1H), 2.13-2.09 (m, 4H), 2.08 (s, 2H), 1.96-1.85 (m, 1H),1.76 (s, 3H), 1.61 (s, 1H), 1.53-1.49 (m, 5H), 1.38 (s, 9H), 1.32-1.20(m, 10H), 0.94 (s, 9H) G80

10-[1(2S)-1- [(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]- decanoic acid 629.35 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.56(t, J = 6.1Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H),7.43-7.39 (m, 4H), 5.12 (s, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.51-4.38 (m,2H), 4.35 (s, 1H), 4.22 (dd, J = 15.8, 5.5 Hz, 1H), 3.72-3.61 (m, 1H),2.45 (s, 3H), 2.25-2.07 (m, 3H), 1.93-1.91 (m, 1H), 1.50-1.46 (m, 5H),1.30-1.24 (m, 13H), 0.94 (s, 9H) G81

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(10-I[(2S)- 1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]decanoyl)- 6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1231.85 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.72 (d, J = 8.4Hz, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.41 (q, J= 8.2 Hz, 4H), 7.39-7.30 (m, 11H), 6.72 (d, J = 17.5 Hz, 1 H), 6.46 (d,J = 7.1 Hz, 1H), 6.09 (d, J = 8.4Hz, 1H), 5.14-5.10 (m, 1H), 4.57-4.53(m, 1H), 4.44-4.34 (m, 4 H), 4.22 (dd, J = 15.9, 5.3 Hz, 1H), 4.11 (s,1H), 3.75-3.60 (m, 3H), 3.33- 3.27 (m, 10H), 3.09-3.05 (m, 1H), 2.45 (s,3H), 2.10-2.06 (m, 1H), 1.52- 1.48 (m, 4H), 1.41-1.35 (m, 17H), 1.32-1.24 (m, 12H), 0.94 (s, 9H) G82

tert-butyl N-[(3S,4R)- 1-carbamoyl-4-[[4- (4-[[(2S)-1-[(2S,4S)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl]carbamoyl]pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 864.45 (400MHz, CDCl₃) δ 8.78 (s, 1H), 8.07 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H),7.48-7.37 (m, 4H), 7.25 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H),5.11 (q, J = 7.1 Hz, 1H), 4.89 (d, J = 9.8 Hz, 1H), 4.74 (d, J = 9.0 Hz,1H), 4.59 (dd, J = 10.2, 6.1 Hz, 2H), 4.48 (s, 1H), 4.38 (d, J = 11.5Hz, 1H), 3.96 (dd, J = 11.0, 4.2 Hz, 1H), 3.86 (d, J = 11.0 Hz, 1H),3.69-3.65 (m, 1H), 3.63-3.59 (m, 1H), 2.67-2.63 (m, 2H), 2.57 (s, 3H),2.37-2.33 (m, 1H), 2.29-2.25 (m, 4H), 2.18-2.14 (m, 1H), 2.00-1.96 (m,1H), 1.73-1.65 (m, 4H), 1.52 (s, 3H), 1.45 (s, 9H), 1.22 (s, 3H), 1.07(s, 9H) G83

tert-butyl N- [(5S,8S,10aR)-8- [[(lS)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[7-[3-methyl-1-(1-methyl- 2,6-dioxopiperidin- 3-yl)-2-oxo-1,3- benzodiazol-5-yl]heptanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1004.75 (400 MHz, CDCl₃) δ 7.40-7.17 (m, 10H), 6.93-6.83(m, 2H), 6.70 (d, J = 7.2 Hz, 1H), 6.23 (t, J = 8.4 Hz, 1 H), 5.73 (d, J= 6.3 Hz, 1H), 5.51 (s, 1H), 5.18 (dd, J = 12.8, 5.2 Hz, 1H), 4.61-4.02(m, 4H), 3.89 (d, J = 13.8 Hz, 1H), 3.44 (s, 3H), 3.27 (s, 3H),3.12-3.02 (m, 1H), 2.92-2.79 (m, 1 H), 2.79-2.61 (m, 3H), 2.6-2.42 (m,1H), 2.40-2.12 (m, 3H), 2.11-1.98 (m, 12H), 1.97-1.71 (m, 1H), 1.68-1.55(m, 5H), 1.46 (s, 9H), 1.40-1.35 (m, 5H) G84

tert-butyl N-[(2S)-4- carbamoyl-1-[(9- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]nonyl) oxy]butan-2- yl]carbamate 815.45 (400 MHz, DMSO-d₆)δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.41(q, J = 8.4 Hz, 4H), 7.23 (s, 1H), 6.70 (s, 1H), 6.57 (d, J = 8.7 Hz,1H), 5.13 (d, J = 3.6 Hz, 1H), 4.55 (d, J = 9.4Hz, 1H), 4.49-4.39 (m,2H), 4.36 (s, 1H), 4.23 (dd, J = 15.9, 5.5 Hz, 1H), 3.72-3.61 (m, 2H),3.29-3.16 (m, 2H), 2.46 (s, 3H), 2.31-2.21 (m, 1H), 2.15-2.10 (m, 2H),2.08 (s, 3H), 2.07-2.01 (m, 2H), 1.96-1.88 (m, 1H), 1.74-1.64 (m, 1H),1.55-1.43 (m, 1H), 1.38 (s, 9H), 1.30-1.21 (m, 14H), 0.94 (s, 9H) G85

tert-butyl N-[(2S)-4- carbamoyl-1-[(8- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]octyl) oxy]butan-2- yl]carbamate 801.55 (400 MHz, DMSO-d₆)δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.41(q, J = 8.4 Hz, 4H), 7.23 (s, 1H), 6.70 (s, 1H), 6.57 (d, J = 8.7 Hz,1H), 5.15-5.13 (m, 1H), 4.55 (d, J = 9.3Hz, 1H), 4.48- 4.38 (m, 2H),4.37-4.35 (m, 1H), 4.22 (dd, J = 15.8, 5.4 Hz, 1H), 3.65 (t, J = 8.7 Hz,2H), 3.49-3.45 (m, 1H), 3.40-3.35 (m, 2H), 3.33-3.12 (m, 2H), 2.45 (s,3H), 2.28-2.24 (m, 1H), 2.10-2.04 (m, 3H), 1.92-1.88 (m, 1H), 1.73-1.71(m, 1H), 1.48- 1.44 (m, 6H), 1.38 (s, 9H), 1.28-1.23 (m, 8H), 0.94 (s,9H) G86

tert-butyl ((S)-5- amino-1-((8-(((S)-1- ((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl) pyrrolidin-1-yl)- 3,3-dimethyl-1-oxobutan-2- yl)amino)-8- oxooctyl)oxy)-5- oxopentan-2- yl)carbamate787.60 (400 MHz, DMSO-d₆) δ 9.00 (s, 1 H), 8.57 (t, J = 6.0 Hz, 1H),7.85 (d, J = 9.4 Hz, 1H), 7.46-7.40 (m, 4H), 7.23 (s, 1H), 6.77-6.50 (m,2H), 5.13 (s, 1H), 4.61-4.17 (m, 4H) 3.66 (t, J = 8.8 Hz, 2H), 3.06-2.99(m, 2H), 2.46 (s, 3H), 2.33-1.86 (m, 6H), 1.74- 1.68 (m, 1H), 1.52-1.44(m, 4H), 1.38 (s, 9H), 1.29-1.24 (m, 6H), 1.20- 1.14 (m, 3H), 0.94 (s,9H) G87

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]- 6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1100.35 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.1Hz, 1H), 7.88 (d, J = 9.4 Hz, 1H), 7.82-7.75 (m, 1H), 7.41 (q, J = 8.4Hz, 4H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.08 (s,1H), 6.68 (s, 1H), 6.57 (d, J = 7.2 Hz, 1H), 5.13 (d, J = 3.6 Hz, 1H),4.55 (d, J = 9.4 Hz, 1H), 4.49- 4.28 (m, 6H), 4.24 (d, J = 5.5 Hz, 1 H),4.23-4.12 (m, 1H), 3.80-3.72 (m, 2H), 3.66 (q, J = 12.9, 9.7 Hz, 4H),3.45-3.35 (m, 2H), 3.20-3.09 (m, 1 H), 2.57 (d, J = 6.2 Hz, 3H), 2.45(s, 3H), 2.29 (t, J = 7.0 Hz, 1H), 2.20-2.09 (m, 3H), 2.11-1.97 (m, 5H),1.98- 1.80 (m, 1H), 1.79-1.59 (m, 1H), 1.59- 1.45 (m, 9H), 1.38 (s, 9H),1.06 (dd, J = 6.3, 2.2 Hz, 3H), 0.94 (s, 9H). G88

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(1S)-3- carbamoyl-1-[(7-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]heptyl) carbamoyl]propyl] carbamoyl]-6-oxo-octahydropyrrolo[1,2-a] [1,5]diazocin-5- yl]carbamate 1051.85 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.07 (d, J = 8.1 Hz,1H), 7.84 (dd, J = 10.5, 7.4 Hz, 2H), 7.41 (q, J = 8.4 Hz, 4H), 7.20 (s,1H), 6.74 (s, 1H), 6.58 (d, J = 7.0 Hz, 1H), 5.76 (s, 1H), 5.13 (d, J =3.5 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.49-4.43 (m, 2H), 4.36 (s, 2H),4.27-4.11 (m, 2H), 3.69-3.65 (m, 3H), 3.10-3.02 (m, 1H), 3.00 (dd, J =13.1, 6.3 Hz, 1H), 2.45 (s, 3H), 2.31- 2.20 (m, 2H), 2.18-1.96 (m, 13H),1.96-1.78 (m, 3H), 1.80-1.59 (m, 3H), 1.50-1.46 (m, 2H), 1.38 (s, 9H),1.26-1.22 (m, 8H), 0.94 (s, 9H) G89

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(1S)-3- carbamoyl-1-[(8-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]octyl) carbamoyl]propyl] carbamoyl]-6-oxo-octahydropyrrolo[1,2-a] [1,5]diazocin-5- yl]carbamate 1065.85 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.07 (d, J = 7.8 Hz,1H), 7.90-7.79 (m, 2H), 7.41 (q, J = 8.4 Hz, 4H), 7.21 (s, 1H), 6.75 (s,1H), 6.58 (d, J = 7.0 Hz, 1H), 5.13 (d, J = 3.5 Hz, 1H), 4.55(d, J = 9.4Hz, 1H), 4.51-4.37 (m, 3H), 4.36 (s, 2H), 4.27-4.13 (m, 1H), 4.16 (s,2H), 3.72-3.65 (m, 2H), 3.63 (s, 2 H), 3.32 (s, 1H), 3.09-2.97 (m, 2H),2.45 (s, 3H), 2.29-2.24 (m, 2H), 2.12 (s, 3H), 2.09-2.05 (m, 5H), 2.01(s, 1H), 1.93-1.89 (m, 1H), 1.84 (s, 2H), 1.80-1.66 (m, 1H), 1.65-1.61(m, 1H), 1.49-1.45 (m, 2H), 1.40-1.36 (m, 11H), 1.26-1.21 (m, 10H), 0.94(s, 9H) G90

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(1S)-3- carbamoyl-1-[(9-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]nonyl) carbamoyl]propyl] carbamoyl]-6-oxo-octahydropyrrolo[1,2-a] [1,5]diazocin-5- yl]carbamate 1079.90 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.55 (t, J = 6.1 Hz, 1H), 8.06 (d, J = 7.8 Hz,1H), 7.82 (dd, J = 12.6, 7.3 Hz, 2H), 7.41 (q, J = 8.4 Hz, 4H), 7.19 (s,1H), 6.73 (s, 1H), 6.65-6.53 (m, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.55 (d,J = 9.4 Hz, 1H), 4.51-4.39 (m, 2H), 4.36 (s, 2H), 4.28-4.13 (m, 1H),4.16 (s, 2H), 3.77-3.51 (m, 7H), 3.06- 2.97 (m, 3H), 2.45 (s, 3H), 2.30-2.24 (m, 1H), 2.18-1.99 (m, 10H), 1.96- 1.86 (m, 1H), 1.87-1.81 (m, 2H),1.74-1.68 (m, 1H), 1.57-1.41 (m, 1 H), 1.40-1.36 (m, 11H), 1.25-1.22 (m,12H), 0.94 (s, 9H) G91

tert-butyl N- [(5S,8S,10aR)-8- [[(1R)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[7-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]heptanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 990.60 (400 MHz, CD₃OD) δ 7.44-7.34 (m, 4H), 7.30 (t, J =7.1 Hz, 3H), 7.27- 7.19 (m, 3H), 7.03 (s, 1H), 7.01-6.93 (m, 2H),6.31-6.25 (m, 1H), 5.39-5.24 (m, 1H), 4.49-4.31 (m, 3H), 4.20- 4.07 (m,1H), 3.83 (d, J = 14.1 Hz, 1H), 3.75-3.64 (m, 1H), 3.43 (d, J = 2.0 Hz,1H), 3.41 (s, 3H), 3.24-3.11 (m, 1H), 2.98-2.87 (m, 1H), 2.86-2.65 (m,6H), 2.48 (s, 2H), 2.38-2.20 (m, 5H), 2.20-2.01 (m, 4H), 1.99-1.80 (m,3H), 1.66 (d, J = 18.3 Hz, 5H), 1.46 (s, 9H) G92

N-[(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- (diphenylmethylcarbamoyl)propyl]carbamoyl]- 6-oxo-3-[2- [(1s,4s)-4-[[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]-octahydropyrrolo[1,2-a] [1,5]diazocin-5- yl]carbamate 1016.80 (400 MHz,DMSO-d₆) δ 11.09 (s, 1 H), 8.74 (d, J = 8.3 Hz, 1H), 8.21 (dd, J = 17.3,7.9 Hz, 1H), 7.42-7.17 (m, 11H), 7.05-6.91 (m, 2H), 6.85-6.82 (m, 1H),6.76-6.72 (m, 1H), 6.47 (d, J = 6.7 Hz, 1H), 6.11 (d, J = 8.4 Hz, 1H),5.34 (dd, J = 12.8, 5.4 Hz, 1H), 4.54-4.19 (m, 3H), 4.10-3.95 (m, 1H),3.84-3.80 (m, 2H), 3.33 (s, 3H), 3.23-3.02 (m, 1H), 2.98-2.81 (m, 1H),2.77-2.56 (m, 5H), 2.46-2.22 (m, 1H), 2.10-2.06 (m, 4H), 2.03- 1.88 (m,6H), 1.86-1.55 (m, 5H), 1.45- 1.39 (m, 16H) G93

tert-butyl N- [(55,85,10aR)-8- [[(15)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[2-[(1r,4r)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]-octahydropyrrolo[1,2-a] [1,5]diazocin-5- yl]carbamate 1016.50 (300 MHz,CDCl₃) δ 9.50 (d, J = 10.0 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.74 (d, J= 9.6 Hz, 2H), 7.24 (td, J = 11.8, 9.9, 5.9 Hz, 16H), 6.80 (dq, J =14.6, 8.1 Hz, 4H), 6.52 (d, J = 7.0 Hz, 1H), 6.23-6.14 (m, 1H), 6.02-5.81 (m, 2H), 5.28-5.11 (m, 2H), 4.65 (s, 2H), 4.36 (dd, J = 19.8, 11.7Hz, 2H), 4.00 (d, J = 13.5 Hz, 3H), 3.07 (s, 1H), 2.92-2.34 (m, 8H),2.19 (d, J = 12.8 Hz, 6H), 2.00-1.60 (m, 1 H), 1.46 (d, J = 15.4 Hz,16H) G94

tert-butyl N-1(1S)-3- carbamoyl-1-([[3-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methyl] carbamoyl)propyl] carbamate 848.42(300 MHz, DMSO-d₆) δ 8.98 (s, 1 H), 8.55 (t, J = 6.1 Hz, 1H), 8.26 (t, J= 5.9 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 7.45-7.35 (m, 5H), 7.27 (s, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.11-6.99 (m, 3H), 6.89 (d, J = 7.8 Hz,1H), 6.77 (s, 1H), 5.11 (s, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.50-4.30 (m,3H), 4.25 (d, J = 5.8 Hz, 3H), 3.94-3.87 (m, 1H), 3.69-3.62 (m, 2H),2.57-2.53 (m, 3H), 2.44 (s, 3H), 2.34-2.23 (m, 1H), 2.20-2.00 (m, 3H),1.94-1.82 (m, 1H), 1.76-1.67 (m, 1H), 1.60-1.43 (m, 4H), 1.38 (s, 9H),0.93 (s, 9H) G95

tert-butyl N- [(5S,8S,10aR)-8- [[(3S,4R)-4-1(4- bromophenyl)meth-oxy]-1- carbamoylpentan-3- yl]carbamoyl]-3-[7- [1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]heptanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 993.20, 995.20 (400 MHz, DMSO-d₆) δ 11.09 (s, 1 H), 7.82(t, J = 8.7 Hz, 1H), 7.55-7.49 (m, 2H), 7.29 (dd, J = 8.4, 3.4 Hz, 2H),7.12-6.98 (m, 3H), 6.84 (d, J = 1.6 Hz, 1H), 6.69 (s, 1H), 6.62-6.53 (m,1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.56-4.28 (m, 5H), 4.21-4.04 (m,1H), 3.87-3.46 (m, 4H), 3.41 (p, J = 6.2 Hz, 1H), 3.34 (s, 3H),3.30-3.09 (m, 1H), 2.98-2.84 (m, 1H), 2.77- 2.55 (m, 5H), 2.47-2.37 (m,1H), 2.34- 1.91 (m, 4H), 1.91-1.43 (m, 8H), 1.43-1.27 (m, 15H), 1.06 (d,J = 6.3 Hz, 3H) G96

tert-butyl N- [(5S,8S,10aR)-8- [[(3S,4R)-4- (benzyloxy)-1-carbamoylpentan-3- yl]carbamoyl]-3-[7- [1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]heptanoyl]-6-oxo-octahydropyrrolo[1,2-a] [1,5]diazocin-5- yl]carbamate 915.35 (400 MHz,DMSO-d₆) δ 11.09 (s, 1 H), 7.82 (dd, J = 9.2, 6.7 Hz, 1H), 7.37- 7.23(m, 5H), 7.14-6.96 (m, 3H), 6.88-6.83 (m, 1H), 6.68 (s, 1H), 6.58 (d, J= 6.9 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.56-4.27 (m, 6H),4.24-4.04 (m, 1H), 3.91-3.63 (m, 4 H), 3.63-3.37 (m, 2H), 3.32 (s, 3H),3.28-3.06 (m, 1H), 2.97-2.85 (m, 2H), 2.82-2.55 (m, 6H), 2.43 (d, J =9.7 Hz, 1H), 2.35-2.23 (m, 1H), 2.22-2.09 (m, 4H), 2.04-1.95 (m, 1H),1.91- 1.69 (m, 2H), 1.69-1.45 (m, 2H), 1.39 (s, 9H), 1.38-1.29 (m, 4H),1.07 (d, J = 6.3, 3H) G97

tert-butyl ((2R,35)- 6-amino-2-((3- fluoro-4-(5-(((S)-1-((2S,4R)-4-hydroxy- 2-(((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1- oxobutan-2- yl)amino)-5-oxopentyl)benzyl)oxy)- 6-oxohexan-3- yl)carbamate 881.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 9.3 Hz,1H), 7.47-7.35 (m, 4H), 7.26- 7.16 (m, 2H), 7.08 (t, J = 10.7 Hz, 2H),6.71-6.61 (m, 2H), 5.09 (d, J = 3.6 Hz, 1H), 4.96-4.88 (m, 1H), 4.51 (d,J = 9.2 Hz, 1H), 4.44 (d, J = 9.1 Hz, 3H), 4.28 (s, 1H), 3.60 (s, 2 H),3.48-3.39 (m, 2H), 2.58 (s, 3H), 2.46 (s, 3H), 2.33-2.26 (m, 1H), 2.18-2.10 (m, 1H), 2.04-1.99 (m, 1H), 1.89- 1.71 (m, 1H), 1.52 (s, 8H), 1.41-1.36 (m, 11H), 1.06 (d, J = 6.2 Hz, 3 H), 0.93 (s, 9H) G98

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 849.50 ¹H NMR (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 9.3Hz, 1H), 7.47-7.39 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.26 (s, 1H), 7.16(t, J = 7.9 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.78-6.69 (m, 4H), 5.10(d, J = 3.5 Hz, 1H), 4.92 (p, J = 7.4, 6.5 Hz, 1H), 4.52 (d, J = 9.3 Hz,1H), 4.43 (t, J = 8.1 Hz, 1H), 4.29 (s, 1H), 3.84 (qd, J = 9.6, 5.9 Hz,2H), 3.74-3.59 (m, 2H), 3.18 (d, J = 5.3 Hz, 2H), 2.46 (s, 3H), 2.26 (m,1H), 2.17-2.07 (m, 3H), 2.10- 1.96 (m, 1H), 1.80 (m, 2H), 1.69-1.45 (m,6H), 1.39 (d, J = 2.4 Hz, 9H), 1.37 (s, 3H), 1.32-1.22 (m, 2H), 0.93 (s,9H) G99

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[2- fluoro-4-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 867.30 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.88 (d, J = 9.3Hz, 1H), 7.47-7.36 (m, 5H), 7.33 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H),7.01-6.98 (m, 2H), 6.67 (s, 1H), 6.58 (d, J = 8.8 Hz, 1H), 5.12 (s, 1H),4.61- 4.39 (m, 6H), 4.35 (s, 1H), 4.22 (dd, J = 15.8, 5.3 Hz, 1H),3.72-3.60 (m, 2H), 3.41 (t, J = 5.8 Hz, 2H), 2.57 (t, J = 7.1 Hz, 1H),2.45 (s, 3H), 2.37-2.25 (m, 1H), 2.20-1.84 (m, 4H), 1.81-1.72 (m, 1H),1.58-1.43 (m, 5H), 1.38 (s, 9H), 1.06 (d, J = 5.6 Hz, 3H), 0.94 (s, 9H)G100

tert-butyl N- [(5S,8S,10aR)-8- [[(LS)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[8-[2-(1- methyl-2,6-dioxopiperidin-3- yl)-1-oxo-3H- isoindol-4-yl]oct-7- ynoyl]-6-oxo-octahydropyrrolo[1,2- a][1,5]diazocin-5- yl]carbamate 999.00 (400 MHz,CDCl₃) δ 7.81 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.60-7.55(m, 1H), 7.46-7.42 (m, 1H), 7.36-7.28 (m, 6H), 7.28-7.24 (m, 5H),6.31-6.21 (m, 1H), 5.76- 5.70 (m, 1H), 5.52-4.45 (m, 1H), 5.25-5.16 (m,1H), 4.57-4.31 (m, 2H), 4.26-4.24 (m, 1H), 4.07-3.95 (m, 3H), 3.89 (s,3H), 3.20-2.81 (m, 3H), 258-2.52 (m, 4H), 2.50-2.40 (m, 4H), 2.23-2.18(m, 3H), 2.09- 1.95 (m, 2H), 1.85-1.61 (m, 8H), 1.52-1.49 (m, 2H), 1.45(s, 9H) G101

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[4-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]butanoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 948.30 (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.74 (d, J = 8.4Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.34-7.24 (m, 11H), 6.99-6.95 (m,2H), 6.93-6.84 (m, 1 H), 6.74 (d, J = 17.2 Hz, 1H), 6.53 (d, J = 6.8 Hz,1H), 6.09 (d, J = 8.4 Hz, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H),4.52-4.25 (m, 3H), 4.24-4.09 (m, 1H), 3.80-3.64 (m, 1H), 3.58 (s, 3H),3.29-3.22 (m, 1H), 3.13 (t, J = 12.7 Hz, 1H), 2.97-2.89 (m, 2H), 2.88-2.82 (m, 1H), 2.77-2.58 (m, 3H), 2.18-2.05 (m, 3H), 2.03-1.95 (m, 3 H),1.95-1.81 (m,4H), 1.82-1.70 (m, 3H), 1.67-1.55 (m, 2H), 1.39 (s, 9H)G102

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[6-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]hexanoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 976.45 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.73 (d, J = 8.4Hz, 1H), 8.19 (t, J = 8.2 Hz, 1H), 7.40-7.18 (m, 9.4 Hz, 11H), 6.96 (q,J = 7.9, 5.6 Hz, 2H), 6.91-6.84 (m, 1H), 6.78-6.58 (m, 1H), 6.46 (d, J =6.7 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.38 (dd, J = 12.7, 5.3 Hz, 1H),4.50-4.26 (m, 3H), 4.18- 3.99 (m, 2H), 3.73 (d, J = 14.3 Hz, 1H), 3.56(s, 3H), 3.29-3.17 (m, 1H), 3.16-3.08 (m, 1H), 2.89 (q, J = 6.6 Hz, 3H),2.78-2.68 (m, 1H), 2.68- 2.59 (m, 1H), 2.47 (d, J = 7.6 Hz, 2H),2.21-2.06 (m, 3H), 2.05-1.96 (m, 3H), 1.97-1.88 (m, 1H), 1.84-1.72 (m,2H), 1.68-1.56 (m, 5H), 1.48-1.42 (m, 1H), 1.37 (s, 9H), 1.19 (t, J =7.2 Hz, 2H) G103

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[7-[3-methyl-1-(1-methyl- 2,6-dioxopiperidin- 3-yl)-2-oxo-1,3- benzodiazol-5-yl]heptanoyl]-6-oxo- octahydropyrrolo[1,2-a] [1,5]diazocin-5-yl]carbamate 1004.75 (400 MHz, CDCl₃) δ 7.40-7.17 (m, 10H), 6.93-6.83(m, 2H), 6.70 (d, J = 7.2 Hz, 1H), 6.23 (t, J = 8.4 Hz, 1H), 5.73 (d, J= 6.3 Hz, 1H), 5.51 (s, 1H), 5.18 (dd, J = 12.8, 5.2 Hz, 1H), 4.61-4.02(m, 4H), 3.89 (d, J = 13.8 Hz, 1H), 3.44 (s, 3H), 3.27 (s, 3H),3.12-3.02 (m, 1H), 2.92-2.79 (m, 1H), 2.79-2.61 (m, 3H), 2.6-2.42 (m,1H), 2.40-2.12 (m, 3H), 2.11- 1.98 (m, 12H), 1.97-1.71 (m, 1H),1.68-1.55 (m, 5H), 1.46 (s, 9H), 1.40-1.35 (m, 5H). G104

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-[9-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]nonanoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1018.45 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.74 (d, J =8.7 Hz, 1H), 8.19 (t, J = 7.9 Hz, 1H), 7.39-7.20 (m, 11H), 7.00-6.91 (m,2H), 6.89-6.84 (m, 1H), 6.76-6.68 (m, 1H), 6.48 (d, J = 6.9 Hz, 1H),6.10 (d, J = 8.4 Hz, 1H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H), 4.48-4.23 (m,3H), 4.19-4.06 (m, 2H), 3.71-3.62 (m, 2H), 3.55 (s, 3H), 3.14-3.06 (m,1H), 2.96-2.83 (m, 3H), 2.78-2.58 (m, 2H), 2.48-2.42 (m, 1H), 2.22-2.06(m, 3H), 2.03-1.97 (m, 3H), 1.95-1.89 (m, 1H), 1.85-1.67 (m, 3H),1.63-1.57 (m, 3H), 1.56- 1.48 (m, 2H), 1.42-1.28 (m, 18H) G105

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(4-[1-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]azetidin-3- yl]butanoyl)-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1003.35 (400 MHz, DMSO-d₆) δ 11.05 (s,1H), 8.73 (d, J = 8.6 Hz, 1H), 8.22-8.13 (m, 1H), 7.38-7.28 (m, 6H),7.28- 7.25 (m, 3H), 7.25-7.22 (m, 1H), 7.21 (s, 1H), 6.96-6.89 (m, 1H),6.72 (d, J = 16.2 Hz, 1H), 6.51 (d, J = 6.9 Hz, 1H), 6.28 (dd, J = 3.8,2.1 Hz, 1H), 6.15-6.04 (m, 2H), 5.27 (dd, J = 12.8, 5.4 Hz, 1H),4.50-4.43 (m, 1H), 4.42-4.35 (m, 1H), 4.32 (t, J = 7.0 Hz, 1H),4.20-4.07 (m, 1H), 3.95-3.87 (m, 2H), 3.76-3.68 (m, 1H), 3.42- 3.36 (m,3H), 3.28 (s, 3H), 3.19-2.98 (m, 2H), 2.97-2.83 (m,1H), 2.74-2.57 (m,3H), 2.49-2.41 (m, 2H), 2.14 (d, J = 5.7 Hz, 1H), 2.12 (d, J = 6.1 Hz,1H), 2.03-1.88 (m, 4H), 1.82-1.70 (m, 3H), 1.68-1.46 (m, 6H), 1.38 (s,9H) G106

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(4-[1-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]piperidin-4- yl]butanoyl)-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1031.40 (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 7.5Hz, 1H), 7.37-7.22 (m,11H), 6.93 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.78-6.69 (m,1H), 6.65- 6.58 (m, 1H), 6.50 (d, J = 6.8 Hz, 1H), 6.10 (d, J = 8.4 Hz,1H), 5.29 (dd, J = 12.9, 5.4 Hz, 1H), 4.50-4.23 (m, 3H), 4.17-4.08 (m,1H), 3.72 (d, J = 14.1Hz, 2H), 3.62-3.56 (m, 3H), 3.30 (s, 3H),3.20-3.08 (m, 2H), 2.97-2.77 (m, 2H), 2.76-2.56 (m, 4H), 2.48-2.42 (m,2H), 2.17-2.10 (m, 2H), 2.09-2.04 (m, 2H), 2.02-1.97 (m, 1H), 1.97-1.88(m, 2H), 1.80-1.72 (m, 3H), 1.64-1.56 (m, 4H), 1.39 (s, 9H), 1.32-1.24(m, 4H) G107

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(6-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]amino]hexanoyl)- 6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 991.35 (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.73 (d, J = 8.5Hz, 1H), 8.19 (d, J = 6.4 Hz, 1H), 7.44-7.13 (m, 12H), 6.85-6.68 (m,2H), 6.51 (d, J = 6.7 Hz, 1H), 6.42-6.36 (m, 1H), 6.31-6.26 (m, 1H),6.10 (d, J = 8.4 Hz, 1H), 5.24 (dd, J = 12.7, 5.3 Hz, 1H), 4.48- 4.50(m, 3H), 4.16-4.09 (m, 1H), 3.81- 3.58 (m, 2H), 3.25 (s, 3H), 2.95- 2.78(m, 3H), 2.76-2.54 (m, 3H), 2.52- 2.47 (m, 3H), 2.39-2.27 (m, 1H), 2.15-2.08 (m, 3H), 2.02-1.86 (m, 4H), 1.62-1.56 (m, 7H), 1.42-1.34 (m, 1 1H)G108

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(4-[4-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]piperazin-1- yl]butanoyl)-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1032.55 (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 7.5Hz, 1H), 7.18-7.38 (m,11H), 6.95 (d, J = 8.5 Hz, 1H), 6.87-6.83 (m, 1H), 6.77 (d, J = 8.9 Hz,1H), 6.72-6.56 (m, 2H), 6.10 (d, J = 8.5 Hz, 1H), 5.30 (dd, J = 12.9,5.4 Hz, 1H), 4.55-4.49 (m, 1H), 4.47-4.25 (m, 3H), 4.18-4.14 (m, 1H),3.86-3.61 (m, 3H), 3.31 (s, 3H), 3.20-3.14 (m, 4H), 2.97-2.82 (m, 2H),2.79-2.57 (m, 6H), 2.45-2.26 (m, 2H), 2.23-2.06 (m, 4H), 2.05-1.92 (m,4H), 1.86- 1.52 (m, 6H), 1.38 (s, 9H) G109

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(3-[4-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]piperazin-1- yl]propanoyl)-6- oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1018.30 (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 8.64 (d, J = 8.7 Hz, 1H), 8.30-8.18 (m, 1H), 7.37-7.21 (m, 11H),6.98 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.83-6.78 (m, 1H),6.68 (d, J = 8.5 Hz, 2H), 6.10 (d, J = 8.3 Hz, 1H), 5.34-5.29 (m, 1H),4.72-4.15 (m, 4H), 3.74-3.50 (m, 5H), 3.31 (s, 3H), 3.23-3.14 (m, 1H),2.96-2.80 (m, 5H), 2.68-2.63 (m, 3H), 2.34 (d, J = 1.9 Hz, 1H),2.22-2.06 (m, 6H), 2.05-1.80 (m, 4H), 1.72-1.69 (m, 1H), 1.68-1.49 (m,4H), 1.40 (s, 9H) G110

tert-butyl N-[(2S)-4- carbamoyl-1-[(8- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]oct-2- yn-1-yl)oxy]butan- 2-yl]carbamate 797.30 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.89 (d, J = 9.3 Hz,1H), 7.48-7.38 (m, 5H), 7.24 (s, 1H), 6.71 (s, 1H), 6.64 (d, J = 8.6 Hz,1H), 5.13 (d, J = 3.6 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.45- 4.42 (m,2H), 4.36-4.34 (m, 1H), 4.22 (dd, J = 15.8, 5.4 Hz, 1H), 4.09 (s, 2H),3.72-3.59 (m, 2H), 3.51-3.48 (m, 1H), 3.23-3.29 (m, 3H), 2.45 (s, 3H),2.33-2.17 (m, 2H), 2.17-1.98 (m, 4H), 1.92-1.89 (m, 1H), 1.79- 1.65 (m,1H), 1.48-1.38 (m, 4H), 1.38 (s, 9H), 1.35-1.31 (m, 1H), 0.94 (s, 9H).G111

tert-butyl N-[(2S)-4- carbamoyl-1-[[(22)- 8-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]oct-2- en-1-yl]oxy]butan- 2-yl]carbamate 799.30 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.86 (d, J = 9.3 Hz,1H), 7.41 (q, J = 8.4 Hz, 5H), 7.23 (s, 1H), 6.78-6.59 (m, 1H), 6.60 (d,J = 8.6 Hz, 1H), 5.54-5.41 (m, 2H), 5.20-5.09 (m, 1H), 4.55 (d, J = 9.3Hz, 1H), 4.50-4.39 (m, 2H), 4.36(s, 1H), 4.22 (dd, J = 15.9,5.4 Hz, 1H),3.96 (d, J = 5.6 Hz, 2H), 3.76- 3.56 (m, 2H), 3.55-3.43 (m, 2H),3.29-3.12 (m, 3H), 2.45 (s, 3H), 2.32- 2.22 (m, 1H), 2.16-2.00 (m, 6H),1.95-1.88 (m, 1H), 1.75-1.59 (m, 1 H), 1.53-1.44 (m, 1H), 1.38 (s, 9H),1.34-1.16 (m, 2H), 0.94 (s,9H), 0.93- 0.88 (m, 1H) G112

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(3- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]-carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl)- phenoxy]butan-2- yl]carbamate 821.60 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 9.3 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.29-7.24 (m,1H), 7.22-7.14 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 7.2, 4.7Hz, 4H), 5.10 (d, J = 3.6 Hz, 1 H), 4.93 (p, J = 6.9 Hz, 1H), 4.54 (d, J= 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.34 (d, J = 4.2 Hz, 1H), 4.29(s, 1H), 3.87-3.83 (m, 2H), 3.81-3.69 (m, 1H), 3.63 (d, J = 3.3 Hz, 2H),2.46 (s, 3H), 2.30-2.26 (m, 1H), 2.22- 2.08 (m, 2H), 2.04-2.00 (m, 1H),1.86- 1.71 (m, 3H), 1.62-1.58 (m, 1H), 1.42-1.35 (m, 14H), 1.27-1.23 (m,1H), 0.95 (s, 9H) G114

tert-butyl N-[(2S)-4- carbamoyl-1-[4- chloro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 883.60 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.1 Hz,1H), 7.48-7.36 (m, 4H), 7.40-7.24 (m, 2H), 7.28-7.24 (m, 1H), 6.90 (d, J= 3.1 Hz, 1H), 6.86-6.71 (m, 2H), 5.12-5.08 (m, 1H), 4.92 (d, J = 7.4Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (d, J = 8.0 Hz, 1H), 4.31- 4.27(m, 1H), 3.85 (d, J = 6.5 Hz, 1H), 3.73-3.69 (m, 1H), 3.63-3.59 (m, 1H),2.62 (d, J = 7.7 Hz, 1H), 2.45 (s, 3H), 2.27 (d, J = 15.1, 7.7 Hz, 1H),2.16-2.06 (m, 3H), 2.01 (d, J = 10.0 Hz, 1H), 1.80-1.78(m, 2H), 1.52-1.53 (m, 4H), 1.37 (s, 9H), 1.35-1.27 (m, 2H), 1.2-1.23 (m, 4H), 0.94(s, 9H), 0.90-0.76 (m, 3H) G115

tert-butyl N-[(2S)-4- carbamoyl-1-[2- chloro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 883.60 (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.42-8.33 (m, 2H), 7.79 (d, J = 9.2 Hz, 1H),7.44-7.40 (m, 4H), 7.28 (d, J = 7.9 Hz, 1H), 7.02-6.96 (m, 2H),6.79-6.75 (m, 2H), 5.11-5.02 (m, 1H), 4.99-4.88 (m, 2H), 4.58-4.48 (m,2H), 4.49-4.38 (m, 2H), 4.32-4.26 (m, 1H), 3.98-3.87 (m, 2H), 3.81-3.71(m, 1H), 3.62-3.50 (m, 2H), 2.45 (s, 3H), 2.35-2.18 (m, 1H), 2.14-2.10(m, 2H), 2.08 (s, 3H), 2.00-1.98 (m, 1H), 1.88-1.73 (m, 2H), 1.60-1.44(m, 5H), 1.39-1.37 (m, 7H), 1.25-1.23 (m, 4H), 0.94 (s, 9H) G116

tert-butyl N-[(3R)-1- carbamoyl-5-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]pentan-3- yl]carbamate 847.70 (300 MHz,DMSO-d6) δ 8.97 (s, 1 H), 8.34 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 9.2 Hz,1H), 7.40 (q, J = 8.4 Hz, 4H), 7.27-7.09 (m, 2H), 6.97 (d, J = 7.0 Hz,3H), 6.67 (d, J = 8.7 Hz, 2H), 5.08 (d, J = 3.5 Hz, 1H), 4.93 (q, J = 12Hz, 1H), 4.54-4.37 (m, 2H), 4.35-4.26 (m, 1H), 3.60 (d, J = 3.6 Hz, 2H),3.42-3.35 (m, 1H), 3.32-3.26 (m, 2H), 2.45 (s, 3H), 2.31-2.18 (m, 1H),2.17-1.94 (m, 4H), 1.85-1.72 (m, 2H), 1.68-1.54 (m, 8H), 1.42- 1.34 (m,12H), 1.32-1.27 (m, 2H), 0.93 (s, 9H) G117

tert-butyl N-[(2S)-4- carbamoyl-1-[3- chloro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 883.15 (400 MHz,DMSO-d₆) δ 8.97 (s, 1 H), 8.35 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 9.2 Hz,1H), 7.47-7.34 (m, 4H), 7.24 (s, 1H), 6.86-6.76 (m, 3H), 6.73 (d, J =2.3 Hz, 2H), 5.08 (d, J = 3.5 Hz, 1H), 5.00-4.85 (m, 1H), 4.51 (d, J =9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.31-4.25 (m, 1H), 3.91-3.83 (m,2H), 3.60 (d, J = 3.4 Hz, 2H), 2.45 (s, 3H), 2.30-2.20 (m, 1H), 2.17-2.07 (m, 4H), 2.03-1.92 (m, 1H), 1.86-1.72 (m, 3H), 1.60-1.46 (m, 6H),1.38 (s, 9H), 1.25 (d, J = 9.7 Hz, 3H), 1.06 (t, J = 12.1 Hz, 2H), 0.92(s, 9H) G118

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)-2- methylphenoxy] butan-2-yl]carbamate 863.45 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.27 (s,1H), 7.03 (t, J = 7.9 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.73 (dd, J =7.9, 4.2 Hz, 3H), 5.10 (d, J = 3.5 Hz, 1H), 4.96-4.88 (m, 1H), 4.52 (d,J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.31-4.25 (m, 1H), 3.89-3.71(m, 3H), 3.64-3.58 (m, 2H), 2.46 (s, 3H), 2.31- 2.23 (m, 1H), 2.18-2.11(m, 3H), 2.10 (s, 3H), 2.04-1.98 (m, 1H), 1.86- 1.76 (m, 2H), 1.68-1.42(m, 3H), 1.40-1.37 (m, 12H), 1.37-1.34 (m, 2H), 1.33-1.20 (m, 2H), 0.94(s, 9H), 0.89-0.82 (m, 2H) G119

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([1-[4-(4- methyl-1,3-thiazol-5- yl)phenyl]cyclopropyl]carbamoyl) pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 861.40 (400 MHz,DMSO-d₆) δ 8.97 (s, 1H), 8.80 (s, 1H), 7.91 (d, J = 9.3 Hz, 1H),7.37-7.28 (m, 4H), 7.26 (s, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.82 (d, J =8.5 Hz, 1H), 6.79-6.69 (m, 4H), 5.13 (d, J = 3.4 Hz, 1H), 4.55 (d, J =9.4 Hz, 1H), 4.41-4.37 (m, 2H), 3.91- 3.77 (m, 2H), 3.65 (d, J = 3.3 Hz,2H), 2.44 (s, 3H), 2.30-2.26 (m, 1H), 2.15-2.11 (m, 3H), 2.05-1.95 (m,1H), 1.89-1.85 (m, 1H), 1.56-1.52 (m, 4H), 1.39 (s, 9H), 1.34-1.20 (m,5H), 1.19-1.07 (m, 2H), 0.94 (s, 9H), 0.91- 0.80 (m, 4H) G120

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 867.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3 Hz,1H), 7.47-7.41 (m, 2H), 7.41- 7.31 (m, 2H), 7.27 (s, 1H), 7.06 (d, J =11.5, 8.2 Hz, 1H), 6.99(d, J = 8.3, 2.0 Hz, 1H), 6.84 (d, J = 8.5 Hz,1H), 6.73 (d, J = 8.2, 4.4, 1.9 Hz, 2H), 5.11 (d, J = 3.6 Hz, 1H), 4.92(d, J = 7.4 Hz, 1H), 4.54-4.50 (m, 1H), 4.44-4.40 (m, 1H), 4.31-4.27 (m,1H), 3.94-3.90 (m, 2H), 3.73 (s, 1H), 3.63-3.59 (m, 2H), 2.46 (s, 3H),2.28- 2.24 (m, 1H), 2.16-2.12 (m, 2H), 2.07-1.96 (m, 4H), 1.82-1.78 (m,2H), 1.57-1.44 (m, 3H), 1.37 (s, 9H), 1.36-1.20 (m, 7H), 0.93 (s, 9H)G121

tert-butyl N-[(1S)- 3-carbamoyl-1-[[3- (5-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 862.55 (300 MHz,DMSO-d₆) δ 9.84 (s, 1H), 8.97 (s, 1H), 8.35 (d, J = 7.8 Hz, 1 H), 7.76(d, J = 9.2 Hz, 1H), 7.45-7.36 (m, 7H), 7.27 (s, 1H), 7.24-7.13 (m, 1H),6.98 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.76 (s, 1H), 5.08(d, J = 3.5 Hz, 1H), 4.96-4.85 (m, 1H), 4.50 (d, J = 9.3 Hz, 1H), 4.42(t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.02 (s, 1H), 3.60 (s, 2H), 3.48-3.35(m, 4H), 2.45 (s, 3H), 2.30-1.95 (m, 4H), 1.95-1.71 (m, 1H), 1.59-1.45(m, 4H), 1.37 (s, 9H), 1.36-1.34 (m, 3H), 1.31-1.23 (m, 2H), 0.92 (s,9H) G122

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pentyl) phenoxy]pentan-3- yl]carbamate 849.60 (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.86 (d, J = 9.3 Hz,1H), 7.48-7.37 (m, 5H), 7.25 (s, 1H), 7.21-7.10 (m, 1H), 6.76- 6.68 (m,5H), 5.13 (d, J = 3.5 Hz, 1H), 4.56 (d, J = 9.3 Hz, 1H), 4.51-4.16 (m,5H), 3.71-3.63 (m, 2H), 3.59- 3.43 (m, 1H), 2.46 (s, 3H), 2.33-2.24 (m,1H), 2.19-1.78 (m, 6H), 1.61- 1.47 (m, 4H), 1.40 (s, 9H), 1.34-1.21 (m,4H), 1.18 (d, J = 6.1 Hz, 3H), 0.95 (s, 9H) G123

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenoxy]butan-2- yl]carbamate 835.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 9.3 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.27 (s, 1H),7.17 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.77-6.70 (m, 4H),5.10 (d, J = 3.6 Hz, 1H), 4.94-4.90 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H),4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.85-3.81 (m, 2H), 3.63-3.59 (m,2H), 2.54 (s, 2H), 2.46 (s, 3H), 2.35- 2.25 (m, 1H), 2.18-2.07 (m, 2H),2.03- 1.98 (m, 1H), 1.81-1.77 (m, 2H), 1.55- 1.51 (m, 7H), 1.39 (s, 9H),1.27- 1.23 (m, 2H), 1.08-1.04 (m, 1H), 0.94 (s, 9H) G124

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 4-methylphenoxy] butan-2-yl]carbamate 863.45 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 9.3Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.27 (s,1H), 7.01 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H),6.69 (d, J = 2.7 Hz, 1H), 6.64 (dd, J = 8.2, 2.7 Hz, 1H), 5.10-5.08 ( m,1H), 4.93-4.91 (m, 1H), 4.53-4.51 (m, 1H), 4.43-4.41( m, 2H), 4.28-4.26(m, 1H), 3.86-3.75 (m, 2H), 3.69-3.67 (m, 2H), 3.61-3.58 (m, 2H),3.32-3.30 (m, 2H), 2.45 (s, 3H), 2.17-2.15 (m, 5H), 1.80-1.78 (m, 2H),1.57-1.46 (m, 4H), 1.38-1.36 (m, 12H), 1.30- 1.22 (m, 4H), 0.94 (s, 9H)G125

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(lS)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 5-methylphenoxy] butan-2-yl]carbamate 863.45 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.27 (s,1H), 6.81 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 6.59-6.51 (m, 3H),5.17-5.03 (m, 1H), 4.94-4.90 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t,J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.83-3.79 (m, 2H), 3.74-3.67 (m, 1H),3.61 (d, J = 3.9 Hz, 2H), 2.46 (s, 3H), 2.23 (s, 3H), 2.14-2.09 (m, 2H),1.87-1.74 (m, 1H), 1.58-1.49 (m, 6H), 1.42-1.35 (m, 13H), 1.25-1.20 (m,6H), 0.93 (s, 9H) G126

tert-butyl N-[(2S)-4- carbamoyl-1-[5-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 2-methylphenoxy] butan-2-yl]carbamate 863.40 (400MHz, Chloroform-d) δ 8.70 (s, 1H), 7.40-7.30 (m, 5H), 7.03 (d, J = 7.6Hz, 1H), 6.69 (d, J = 7.5, 1.5 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 6.5-6.47 (m, 1H), 6.36 (d, J = 8.7 Hz, 1H), 5.75 (s, 1H), 5.32 (s, 1H), 5.10(d, J = 14.9, 7.4 Hz, 2H), 4.72 (s, 1H), 4.58 (d, J = 8.8 Hz, 1H), 4.53(d, J = 4.4, 2.2 Hz, 1H), 4.13-3.94 (m, 4H), 3.63 (d, J = 11.3, 3.8 Hz,1H), 3.50 (s, 1H), 2.56-2.52 (m, 4H), 2.38-2.34 (m, 2H), 2.19-2.10(m,3H), 2.03-1.98 (m, 2H), 1.62-1.59 (m, 3H), 1.49 (d, J = 7.0 Hz, 3H),1.43 (s, 9H), 1.29- 1.25 (m, 3H), 1.04 (s, 9H), 0.91- 0.87 (m, 4H) G127

tert-butyl N-[(2S)-4- carbamoyl-1-[4- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 867.35 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.27 (s, 1H),7.02 (t, J = 9.3 Hz, 1H), 6.86- 6.79 (m, 2H), 6.77-6.73 (m, 2H), 4.94-4.90 (m, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.31-4.27 (m, 1H), 3.84-3.80 (m, 2H), 3.70 (d, J = 10.3 Hz, 1H), 3.61 (d, J =3.7 Hz, 2H), 2.55 (d, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.28-2.24 (m, 1H),2.14- 2.10 (m, 3H), 2.08 (s, 2H), 2.04-2.00 (m, 1H), 1.82-1.78 (m, 1H),1.56- 1.52 (m, 6H), 1.39 (s, 9H), 1.39-1.35 (m, 2H), 1.29-1.25 (m, 2H),0.93 (s, 9H) G128

tert-butyl N-[(2S)-4- carbamoyl-1-[3- fluoro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 867.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3 Hz,1H), 7.49-7.31 (m, 4H), 7.27 (s, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.74 (s,1H), 6.60 (d, J = 9.1 Hz, 3H), 5.11 (s, 1H), 4.94-4.90 (m, 1H), 4.55-4.47 (m, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.92-3.80 (m, 2H),3.74-3.67 (m, 1H), 3.66-3.55 (m, 2H), 2.54 (s, 1H), 2.46 (s, 3H), 2.30-2.20 (m, 1H), 2.17-2.07 (m, 3H), 2.10- 1.96 (m, 1H), 1.82-1.78 (m, 3H),1.67-1.44 (m, 6H), 1.40-1.36 (m, 11H), 1.28-1.24 (m, 2H), 0.93 (s, 9H)G129

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl)-3- methylphenyl] methoxy]pentan-3- yl]carbamate877.35 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.83(d, J = 9.3 Hz, 1H), 7.47-7.41 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.22(s, 1H), 7.07 (d, J = 10.3 Hz, 3H), 6.69 (s, 1H), 6.60 (d, J = 9.2 Hz,1H), 5.10(s, 1H), 4.96-4.89 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.48-4.35(m, 3H), 4.28 (s, 1H), 3.65-3.56 (m, 2H), 3.46-3.37 (m, 3H), 2.56-2.54(m, 1H), 2.46 (s, 3H), 2.37-2.27 (m, 1H), 2.24 (s, 3H), 2.21-1.95 (m,4H), 1.83-1.77 (m, 2H), 1.59-1.44 (m, 6H), 1.39 (s, 9H), 1.37-1.36(m,2H), 1.05 (d, J = 6.0 Hz, 3H), 0.94 (s, 9H) G130

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]pentan-3- yl]carbamate 863.50 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 9.2 Hz,1H), 7.47-7.35 (m, 4H), 7.25 (s, 1H), 7.15 (t, J = 7.7 Hz, 1H),6.80-6.62 (m, 5H), 5.11 (d, J = 3.6 Hz, 1H), 4.96-4.88 (m, 1H), 4.52 (d,J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.32-4.26 (m, 2H), 3.64-3.59(m, 2H), 3.54-3.47 (m, 1H), 2.46 (s, 3H), 2.30-2.21 (m, 1H), 2.16-1.95(m, 7H), 1.94-1.73 (m, 3H), 1.60- 1.47 (m, 5H), 1.38 (s, 9H), 1.31-1.24(m, 3H), 1.17 (d, J = 6.1 Hz, 3H), 0.93 (s, 9H) G131

tert-butyl N-[(1S)- 3-carbamoyl-1-([[3- (5-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]methyl] carbamoyl)propyl] carbamate 876.70(400 MHz,Methanol-d₄) δ 8.89 (s, 1H), 7.48-7.42 (m, 4H), 7.22 (t, J =7.5 Hz, 1H), 7.11 (dd, J = 19.7, 9.7 Hz, 3H), 5.02 (q, J = 7.0 Hz, 1H),4.68- 4.63 (m, 1H), 4.59 (t, J = 8.3 Hz, 1H), 4.48-4.43 (m, 1H), 4.36(t, J = 15.6 Hz, 2H), 4.14-4.06 (m, 1H), 3.90 (d, J = 11.0 Hz, 1H), 3.77(dd, J = 11.0, 3.9 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 2.50 (s, 3H), 2.32(d, J = 2.1 Hz, 1H), 2.31-2.27 (m, 2H), 2.26-2.20 (m, 1H), 2.09-2.02 (m,1H), 1.98 (ddd, J = 13.2, 9.0, 4.5 Hz, 1H), 1.93- 1.85 (m,1H), 1.69-1.61(m, 4H), 1.59- 1.48 (m, 4H), 1.46 (s, 9H), 1.37 (d, J = 7.9 Hz, 2H),1.06-1.03 (m, 9H) G132

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]butyl) phenoxy]butan-2- yl]carbamate 821.30 (400 MHz,Methanol-d₄) δ 8.90 (s, 1H), 7.52-7.39 (m, 4H), 7.16 (t, J = 8.0 Hz,1H), 6.81-6.70 (m, 3H), 4.68- 4.46 (m, 4H), 4.37 (d, J = 15.6 Hz, 1H),3.99-3.76 (m, 5H), 2.60 (t, J = 6.9 Hz, 2H), 2.49 (s, 3H), 2.40-2.18 (m,5H), 2.14-1.95 (m, 2H), 1.80 (s, 1H), 1.65 (t, J = 6.0 Hz, 4H), 1.46 (s,9H), 1.05 (s, 9H) G133

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4- methyl-1,3-thiazol-5- yl)phenoxy]carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl)phenyl]methoxy]pentan- 3-yl]carbamate 862.40 ¹H NMR (400 MHz,Methanol-d₄) δ 8.89 (s, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.14 (s, 1H), 7.12-7.05 (m, 2H), 4.66(d, J = 5.8 Hz, 1H), 4.62-4.55 (m, 1H), 4.54-4.51 (m, 2H), 4.42-4.40 (m,2H), 4.37-4.31 (m, 2H), 4.13-4.09 (m, 1H), 3.93- 3.91 (m, 1H), 3.82 (dd,J = 10.9, 3.9 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 2.39-2.21 (m, 6H),2.15-2.01 (m, 1H), 1.92-1.88 (m, 1H), 1.68-1.60 (m, 4H), 1.45 (s, 9H),1.39-1.35 (m, 2H), 1.05 (s, 9H). G134

tert-butyl N-[(3R)-1- carbamoyl-5-[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl]pentyl) phenyl]pentan-3- yl]carbamate 833.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.84 (d, J = 9.3 Hz,1H), 7.41 (q, J = 8.4 Hz, 4H), 7.22 (s, 1H), 7.16 (t, J = 7.5 Hz, 1H),6.98 (d, J = 7.4 Hz, 3H), 6.69 (d, J = 9.0 Hz, 2H), 5.13 (s, 1H), 4.55(d, J = 9.4 Hz, 1H), 4.50-4.40 (m, 2H), 4.37 (s, 1H), 4.23 (dd, J =15.9, 5.4 Hz, 1H), 3.73-3.62 (m, 2H), 2.54 (s, 2H), 2.46 (s, 3H),2.34-2.22 (m, 1H), 2.13 (dd, J = 13.9, 6.7 Hz, 2H), 2.04 (t, J = 7.6 Hz,3H), 1.97-1.86 (m, 1H), 1.64 (d, J = 8.0 Hz, 2H), 1.62- 1.45 (m, 7H),1.41 (s, 9H), 1.38- 1.34 (m, 1H), 1.29 (q, J = 7.5 Hz, 2H), 0.94 (s, 9H)G135

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[2- fluoro-4-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 881.55 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 9.2Hz, 1H), 7.47-7.36 (m, 4H), 7.34 (t, J = 8.0 Hz, 1H), 7.21 (s, 1H),7.04-6.95 (m, 2H), 6.68 (s, 1H), 6.60 (d, J = 8.8 Hz, 1H), 5.10 (s, 1H),4.96- 4.89 (m, 1H), 4.57-4.38 (m, 5H), 4.28 (s, 1H), 3.64-3.57 (m, 2H),3.44- 3.40 (m, 1H), 2.58 (t, J = 7.2 Hz, 1H), 2.46 (s, 3H), 2.37-2.24(m, 1H), 2.21-1.93 (m, 4H), 1.84-1.68 (m, 2H), 1.61-1.42 (m, 5H),1.38-1.35 (m, 13H), 1.06 (d, J = 5.7 Hz, 3H), 0.94 (s, 9H) G136

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl)- 2-methylphenyl] methoxy]pentan-3- yl]carbamate877.51 (400 MHz, Methanol-d₄) δ 8.89 (s, 1H), 7.48-7.41 (m, 4H), 7.21(d, J = 7.6 Hz, 1H), 7.00 (q, J = 8.0 Hz, 2H), 5.51 (s, 2H), 5.02 (q, J= 6.9 Hz, 1H), 4.64 (s, 1H), 4.61-4.55 (m, 2H), 4.50- 4.43 (m, 2H), 3.89(d, J = 10.9 Hz, 1H), 3.76 (dd, J = 11.0, 4.0 Hz, 1H), 3.60-3.55 (m,1H), 3.55-3.49 (m, 1H), 2.59 (d, J = 7.2 Hz, 2H), 2.50 (s, 3H), 2.34 (s,3H), 2.30-2.17(m, 4H), 2.01-1.93 (m, 2H), 1.65 (d, J = 1.6 Hz, 4H), 1.52(d, J = 7.0 Hz, 3H), 1.45 (d, J = 3.7 Hz, 9H), 1.19 (d, J = 6.1 Hz, 3H),1.06 (s, 9H) G137

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4- methyl-1,3-thiazol-5- yl)phenoxy]carbamoyl]pyrrolidin- 1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamate 851.50 (400MHz, Methanol-d₄) δ 8.87 (s, 1H), 7.44-7.39(m, 2H), 7.37-7.32(m, 2H),7.27 (d, J = 7.9 Hz, 2H), 7.17(d, J = 7.8 Hz, 2H), 4.65 (s, 1H), 4.59-4.53 (m, 3H), 4.48 (d, J = 11.5 Hz, 1H), 3.95(d, J = 10.9 Hz, 1H), 3.83(d d, J = 11.0, 3.8 Hz, 1H), 3.61-3.55 (m, 1H), 3.52 (s, 1H), 2.64(d, J= 7.0 Hz, 2H), 2.50-2.44 (m, 4H), 2.38-2.13 (m, 6H), 2.00-1.95(m, 1H),1.66 (s, 4H), 1.45 (s, 9H), 1.17 (d, J = 6.2 Hz, 3H), 1.05 (s, 9H) G138

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 839.40 ¹H NMR (400MHz, CD3OD) δ 8.91- 8.89 (m, 1H), 7.48-7.41 (m, 4H), 7.03-6.93 (m, 2H),6.85-6.82 (m, 1H), 5.03-5.01 (m, 1H), 4.66-4.64 (m, 1H), 4.61-4.56 (m,1H), 4.47-4.42 (m, 1H), 4.02-3.99 (m, 2H), 3.90 (d, J = 10.9 Hz, 2H),3.79-3.76 (m, 1H), 2.71-2.67 (m, 2H), 2.50 (s, 3H), 2.34- 2.32 (m, 4H),2.24-2.18 (m, 1H), 2.06-1.89 (m, 4H), 1.85-1.81 (m, 1H), 1.53 (d, J =7.0 Hz, 3H), 1.46 (s, 9H), 1.05 (s, 9H) G139

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl)- 5-methylphenoxy] butan-2-yl]carbamate 853.40 ¹HNMR (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.84(d, J = 9.2 Hz, 1H), 7.40 (q, J = 8.2 Hz, 4H), 7.25 (s, 1H), 6.83-6.76(m, 2H), 6.72 (s, 1H), 6.59 (d, J = 6.1 Hz, 1H), 5.08 (s, 1H), 4.99-4.85(m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s,1H), 3.88 (d, J = 6.0 Hz, 2H), 3.78-3.66 (m, 1H), 3.64-3.56 (m, 2H),2.45 (s, 3H), 2.28 (d, J = 6.9 Hz, 1H), 2.23 (s, 3H), 2.20-2.10 (m, 4H),2.02-1.95 (m, 1H), 1.87-1.67 (m, 5H), 1.66- 1.52 (m, 1H), 1.38 (s, 9H),1.35 (s, 3H), 0.94 (s, 9H) G140

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl)- 5-methylphenoxy] butan-2-yl]carbamate 867.45 (300MHz, DMSO-d₆) δ 9.00 (d, J = 1.4 Hz, 1H), 8.39 (d, J = 7.7 Hz, 1H), 7.84(d, J = 9.3 Hz, 1H), 7.50-7.37 (m, 4H), 7.28 (s, 1H), 6.81 (dd, J =20.1, 11.0 Hz, 3H), 6.63 (d, J = 5.9 Hz, 1H), 5.12 (s, 1H), 5.01-4.88(m, 1H), 4.57-4.39 (m, 2H), 4.30 (s, 1H), 3.90 (d, J = 5.9 Hz, 2H),3.79- 3.69 (m, 1H), 3.65-3.58 (m, 2H), 2.47 (s, 3H), 2.25 (s, 3H),2.19-2.12 (m, 3H), 2.09 (d, J = 1.5 Hz, 3H), 2.06- 1.98 (m, 1H),1.88-1.73 (m, 3H), 1.67- 1.58 (m, 1H), 1.56-1.44 (m, 4H), 1.40 (s, 9H),1.37 (s, 3H), 0.95 (s, 9H) G141

tert-butyl N-[(3R)-1- carbamoyl-6-[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]hexan-3- yl]carbamate 847.50 (300 MHz,DMSO-d₆) δ 9.00 (s, 1 H), 8.39 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 9.2 Hz,1H), 7.48-7.35 (m, 4H), 7.23 (s, 1H), 7.08 (s, 4H), 6.69 (s, 1 H), 6.60(d, J = 9.2 Hz, 1H), 5.11 (d, J = 3.6 Hz, 1H), 5.01-4.87 (m, 1H),4.59-4.39 (m, 2H), 4.30 (s, 1H), 3.62 (s, 2H), 3.46-3.38 (m, 1 H), 2.49-2.47 (m, 2H), 2.46 (s, 3H), 2.36-1.98 (m, 6H), 1.86-1.73 (m, 1H), 1.66-1.45 (m, 8H), 1.43-1.24 (m, 15H), 0.95 (s, 9H) G142

tert-butyl N-1(1S)-3- carbamoyl-1-[5-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) pyridin-2- yl]propyl]carbamate 820.45 (300 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.42-8.32 (m, 2H), 7.81-7.79 (m, 1H), 7.59-7.56(dd, J = 8.0, 2.3 Hz, 1H), 7.48-7.41 (m, 3H), 7.41-7.32 (m, 2H),7.28-7.23 (m, 1H), 7.21-7.19 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H),5.12-5.11 (d, J = 3.6 Hz, 1H), 4.96-4.89 (m, 1H), 4.53-4.50 (d, J = 9.3Hz, 1H), 4.47-4.41 (s, 2H), 4.29-4.27 (m, 1H), 4.06-4.01 (m, 1H),3.64-3.5δ (m, 2H), 2.69-2.65 (m, 2H), 2.46 (s, 3H), 2.29-2.22 (m, 1H),2.15-2.10 (m, 1H), 2.06-1.2.02 (m, 3H), 2.00 (s, 1H), 1.93-1.74 (m, 2H),1.68-1.61 (m, 2H), 1.56-1.48 (m, 2H), 1.38 (s, 3H), 1.37-1.35 (m, 7H),1.27-1.19 (m, 3H), 0.93 (s, 9H) G143

tert-butyl N-[(2S)-4- carbamoyl-1-[2- chloro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 855.35 (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 9.2 Hz,1H), 7.45-7.41 (m, 4H), 7.29 (s, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.00 (d,J = 8.3 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H),6.76 (s, 1H), 5.12 (s, 1H), 5.00-4.89 (m, 1H), 4.56 (d, J = 9.2 Hz, 1H),4.45 (t, J = 8.1 Hz, 1H), 4.31 (s, 1H), 3.94 (d, J = 5.9 Hz, 2H), 3.79(s, 1H), 3.64 (s, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.48 (s, 3H), 2.34-2.30(m, 1H), 2.25-2.12 (m, 2H), 2.10 (s, 2H), 1.83- 1.79 (m, 4H), 1.65-1.61(m, 1H), 1.41 (s, 9H), 1.37 (d, J = 11.0 Hz, 3H), 0.97 (s, 9H) G144

tert-butyl N-[(2S)-4- carbamoyl-1-[2- chloro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 869.35 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 9.2 Hz,1H), 7.45 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.30 (d, J =15.6 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91(dd, J = 7.6, 1.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.75 (s, 1H), 5.11(d, J = 3.5 Hz, 1H), 4.99-4.87 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.44(t, J = 8.0 Hz, 1H), 4.31-4.27 (m, 1H), 3.93 (d, J = 6.1 Hz, 2H),3.83-3.73 (m, 1H), 3.67-3.56 (m, 2H), 2.71-2.67 (m, 2H), 2.47 (s, 3H),2.36-2.26 (m, 1H), 2.22-2.10 (m, 3H), 2.10-1.97 (m, 1H), 1.92-1.75 (m,2H), 1.70-1.49 (m, 4H), 1.40 (s, 9H), 1.38-1.34 (m, 2H), 1.31-1.22 (m,2H), 0.94 (s, 9H) G145

tert-butyl N-[(2S)-4- carbamoyl-1-[5- chloro-2-fluoro-3-(5-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 901.35 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.81-7.79 (m, 1H),7.44 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H),7.12-7.10 (m, 1H), 6.92-6.90 (m, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.75 (s,1H), 5.11 (s, 1H), 4.92 (p, J = 7.3 Hz, 1H), 4.53-4.51 (m, 1H), 4.42 (t,J = 8.0 Hz, 1H), 4.29 (s, 1H), 3.97- 3.93 (m, 1H), 3.75-3.73 (m, 1H),3.61 (d, J = 4.1 Hz, 2H), 3.27-3.23 (m, 2H), 2.56 (d, J = 7.6 Hz, 1H),2.46 (s, 3H), 2.31-2.20 (m, 1H), 2.19-2.10 (m, 2H), 2.10-2.06 (m, 2H),2.03- 2.01 (m, 1H), 1.88-1.78 (m, 2H), 1.64- 1.44 (m, 5H), 1.38 (s, 9H),1.27-1.21 (m, 4H), 0.93 (s, 9H) G146

tert-butyl N-(3- carbamoyl-1-[[2- chloro-3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]carbamoyl] propyl)carbamate 882.35 (400 MHz,DMSO-d₆) δ 9.31 (s, 1H), 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.84(d, J = 9.3 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.68-7.53 (m, 1H), 7.44(d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.26 (dd, J = 9.8, 6.6Hz, 2H), 7.13 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 5.10 (d, J = 3.6 Hz,1H), 4.92 (p, J = 7.1 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.43 (t, J =8.0 Hz, 1H), 4.29 (s, 1H), 4.12 (s, 1H), 3.61 (d, J = 4.2 Hz, 2H),2.74-2.70 (m, 2H), 2.46 (s, 3H), 2.37-2.29 (m, 1H), 2.21- 2.17 (m, 3H),2.03-1.98 (m, 2H), 1.88- 1.74 (m, 2H), 1.58-1.52 (m, 3H), 1.43-1.35 (m,12H), 1.27-1.23 (m, 1H), 0.94 (s, 9H) G147

tert-butyl N-1(1S)-3- carbamoyl-1-[[2- chloro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenyl]carbamoyl] propyl]carbamate 868.35 (400 MHz,DMSO-d₆) δ 9.32 (s, 1H), 8.99 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 7.90(d, J = 9.3 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H),7.38 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 9.6 Hz, 2H), 7.26 (d, J = 8.1 Hz,1H), 7.15-7.08 (m, 1H), 6.81 (s, 1H), 5.10 (s, 1H), 4.92 (p, J = 6.9 Hz,1H), 4.55 (d, J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H),4.13-4.09 (m, 1H), 3.62 (s, 2H), 2.72- 2.68 (m, 2H), 2.46 (s, 3H),2.35-2.31 (m, 1H), 2.23-2.19 (m, 2H), 2.01 (s, 1H), 1.83-1.79 (m, 4H),1.43-1.35 (m, 12H), 1.33-1.23 (m, 2H), 0.95 (s, 9H) G148

tert-butyl N-1(1S)-3- carbamoyl-1-[[3-(3- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenyl]carbamoyl] propyl]carbamate 834.35 (400 MHz,DMSO-d₆) δ 9.96 (s, 1H), 8.99 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.26(s, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 7.9 Hz, 4H), 7.39 (d, J= 8.3 Hz, 2H), 7.33 (d, J = 3.5 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.04(d, J = 7.8 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.80 (s, 1H), 5.76 (s,1H), 4.93 (p, J = 7.2 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.44 (t, J =8.0 Hz, 1H), 4.29 (p, J = 3.2 Hz, 1H), 4.05 (q, J = 7.5 Hz, 1H), 3.63(d, J = 3.2 Hz, 2H), 2.55 (d, J = 2.7 Hz, 1H), 2.46 (s, 3H), 2.29-2.25(m, 1H), 2.18-2.15 (m, 3H), 2.02-1.99 (m, 1H), 1.96-1.86 (m, 1H),1.85-1.71 (m, 4H), 1.38- 1.21 (m, 12H), 0.95 (s, 9H) G149

tert-butyl N-1(1S)-3- carbamoyl-1-[[2- chloro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 896.45 (300 MHz,DMSO-d₆) δ 9.60 (s, 1H), 9.00 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 7.7 Hz,1H), 7.78 (dd, J = 18.0, 8.8 Hz, 2H), 7.43 (q, J = 8.1 Hz, 4H), 7.32 (s,1H), 7.15-7.01 (m, 3H), 6.82 (s, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.95 (t,J = 7.3Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.45 (t, J = 8.0 Hz, 1H),4.36-4.24 (m, 1H), 4.20-4.15 (m, 1H), 3.63 (s, 2H), 3.36 (d, J = 1.2 Hz,2H), 2.61 (t, J = 7.7 Hz, 2H), 2.48 (s, 3H), 2.31-2.11 (m, 3H),2.10-1.88 (m, 1H), 1.88-1.71 (m, 2H), 1.63-1.48 (m, 2H), 1.46-1.22 (m,14H), 0.95 (s, 9H) G150

tert-butyl N-1(1S)-3- carbamoyl-1-[[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 880.09 (300 MHz,DMSO-d₆) δ 9.32 (s, 1H), 9.00 (d, J = 1.3 Hz, 1H), 8.39 (d, J = 7.7 Hz,1H), 7.78 (dd, J = 18.1,8.6 Hz, 2H), 7.49-7.36 (m, 5H), 7.32- 7.25 (m,2H), 7.14 (d, J = 7.5 Hz, 1H), 6.82 (s, 1H), 5.12 (s, 1H), 5.01-4.86 (m,1H), 4.54 (d, J = 9.1 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.30 (s, 1H),4.17-4.11 (m, 1H), 2.71 (t, J = 7.8 Hz, 2H), 2.48 (s, 3H), 2.34-2.12 (m,3H), 2.07-1.96 (m, 1H), 1.86-1.77 (m, 2H), 1.62-1.50 (m, 4H), 1.46-1.20(m, 18H), 0.95 (s, 9H) G151

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 4-methylphenoxy] butan-2-yl]carbamate 881.40 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.45-7.31 (m, 2H), 7.27 (s, 1H),6.92-6.85 (m, 2H), 6.82 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 5.10 (d, J =3.6 Hz, 1H), 4.92 (p, J = 7.3 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43(t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.89-3.85 (m, 2H), 3.75-3.68 (m, 1H),3.61 (d, J = 4.1 Hz, 2H), 2.58-2.54 (m, 2H), 2.46 (s, 3H), 2.34-2.23 (m,1H), 2.21 (s, 3H), 2.17-2.06 (m, 3H), 2.05- 1.97 (m, 2H), 1.88-1.74 (m,2H), 1.64- 1.44 (m, 5H), 1.38 (s, 9H), 1.36-1.14 (m, 4H), 0.93 (s, 9H)G152

tert-butyl N-[(2S)-4- carbamoyl-1-[2,4- difluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 885.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 9.3 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.45-7.31 (m, 2H), 7.27 (s, 1H),7.05-7.01 (m, 1H), 6.97-6.95 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.74 (s,1H), 5.10 (d, J = 3.5 Hz, 1H), 4.92 (p, J = 7.0 Hz, 1H), 4.51 (d, J =9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.90 (d, J = 6.0Hz, 2H), 3.76- 3.67 (m, 1H), 3.66-3.55 (m, 2H), 2.59 (t, J = 7.5 Hz,2H), 2.46 (s, 3H), 2.32-2.20 (m, 1H), 2.17-2.06 (m, 3H), 2.04-1.98 (m,1H), 1.86-1.74 (m, 2H), 1.64-1.43 (m, 5H), 1.39 (s, 9H), 1.35-1.20 (m,4H), 1.10-1.02 (m, 1H), 0.93 (s, 9H) G153

tert-butyl N-[(2S)-4- carbamoyl-1-[3- (I[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(15)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]methyl) phenoxy]butan-2- yl]carbamate 793.30 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 9.2 Hz,1H), 7.48-7.31 (m, 4H), 7.28 (s, 1H), 7.19 (t, J = 7.9 Hz, 1H), 8.99 (s,1H), 6.94-6.67 (m, 5H), 5.11 (d, J = 3.5 Hz, 1H), 4.99-4.87 (m, 1H),4.52-4.39 (m, 2H), 4.30-4.24 (m, 1H), 3.90-3.67 (m, 3H), 3.66- 3.54 (m,3H), 3.40 (d, J = 13.7 Hz, 1H), 2.46 (s, 3H), 2.18-2.09 (m, 6.4 Hz, 2H),2.03-1.99 (m, 1H), 1.83-1.70 (m, 2H), 1.68-1.54 (m, 1H), 1.42-1.38 (m,10H), 1.38-1.36 (s, 2H), 0.92 (s, 9H) G154

fer-butyl N-1(1S)-3- carbamoyl-1-[[3- chloro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 896.45 (300 MHz,DMSO-d₆) δ 10.07 (s, 1H), 8.97 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.77(d, J = 9.2 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.40 (q, J = 8.3 Hz, 4H),7.28 (s, 2H), 7.06 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 1.7 Hz, 1H), 6.77(s, 1H), 5.09 (d, J = 3.5 Hz, 1H), 4.97-4.86 (m, 1H), 4.51 (d, J = 9.3Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.00 (d, J = 6.9 Hz,1H), 3.60 (s, 2H), 2.53 (d, J = 7.5 Hz, 2H), 2.45 (s, 3H), 2.30-2.10 (m,4H), 2.01-1.74 (m, 4H), 1.65-1.42 (m, 4H), 1.41-1.35 (m, 11H), 1.33-1.19(m, 4H), 0.92 (s, 9H) G155

tert-butyl N-[(1S)-3- carbamoyl-1-[[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 5-methylphenyl] carbamoyl]propyl] carbamate 876.40(300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.00 (s, 1H), 8.37 (d, J = 7.7 Hz,1H), 7.79 (d, J = 92 Hz, 1H), 7.49- 7.38 (m, 4H), 7.29-7.18 (m, 3H),7.00 (d, J = 7.8 Hz, 1H), 6.79-6.72 (m, 2H), 5.10 (d, J = 3.5 Hz, 1H),5.01- 4.83 (m, 1H), 4.63-4.36 (m, 2H), 4.30 (s, 1H), 4.06-3.97 (m, 1H),3.62 (d, J = 3.2 Hz, 2H), 3.04-2.45 (m, 6H), 2.26 (s, 3H), 2.18-2.13 (m,6H), 1.95- 1.70 (m, 2H), 1.62-1.51 (m, 4H), 1.39 (s, 9H), 1.32-1.24 (m,4H), 0.95 (s, 9H) G156

tert-butyl N-1(1S)-3- carbamoyl-1-[[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 2-methylphenyl] carbamoyl]propyl] carbamate 876.50(300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.00 (s, 1H), 8.40 (d, J = 7.7 Hz,1H), 7.82 (d, J = 9.2 Hz, 1H), 7.47-7.34 (m, 6H), 7.23-6.93 (m, 4H),6.82 (s, 1H), 5.13(d, J = 3.5Hz, 1H), 4.96- 4.90 (m, 1H), 4.60-4.38 (m,2H), 4.30 (s, 1H), 4.08 (d, J = 6.8 Hz, 1H), 3.63 (d, J = 3.3 Hz, 2H),2.60 (d, J = 7.6 Hz, 2H), 2.47 (s, 3H), 2.36-1.88 (m, 9H), 1.85-1.81 (m,2H), 1.67-1.46 (m, 4H), 1.41 (d, J = 3.8 Hz, 11H), 1.39-1.14 (m, 2H),0.95 (s, 9H) G157

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(2- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(lS)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]ethyl) phenoxy]butan-2- yl]carbamate 807.3 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 9.3 Hz,1H), 7.44 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.28 (s, 1H),7.16 (t, J = 7.8 Hz, 1H), 6.86- 6.70 (m, 5H), 5.76 (s, 1H), 5.17-5.09(m, 1H), 4.93 (p, J = 7.2 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.44 (t, J= 8.0 Hz, 1H), 4.29 (s, 1H), 3.84 (qd, J = 9.6, 5.8 Hz, 2H), 3.72 (dp, J= 9.0, 4.9 Hz, 1H), 3.62 (d, J = 3.4 Hz, 2H), 3.35-3.32 (m, 4H),2.85-2.69 (m, 2H), 2.60-2.58 (m, 1H), 2.46 (s, 3H), 2.20-1.99 (m, 4H),1.82-1.76 (m, 2H), 1.62-1.57 (m, 1H), 1.44 (s, 9H), 0.90 (s, 9H) G158

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 839.40 (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 9.2 Hz,1H), 7.42 (q, J = 8.3 Hz, 4H), 7.29 (s, 1H), 7.03-6.98 (m, 2H),6.84-6.80 (m, 2H), 6.74 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 4.98-4.88 (m,1H), 4.54 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H),3.93 (d, J = 6.0 Hz, 2H), 3.75-3.73 (m, 1H), 3.64-3.61 (m, 2H), 2.58 (t,J = 7.6 Hz, 2H), 2.47 (s, 3H), 2.32- 2.28 (m, 1H), 2.21-2.16 (m, 2H),2.07- 1.97 (m, 1H), 1.87-1.69 (m, 5H), 1.64-1.62 (m, 1H), 1.40 (s, 9H),0.96 (s, 9H) G159

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenoxy]butan-2- yl]carbamate 853.35 (400 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 9.3 Hz,1H), 7.45 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H),7.06-6.96 (m, 2H), 6.87-6.80 (m, 2H), 6.75 (s, 1H), 5.11 (d, J = 3.5 Hz,1H), 4.94-4.92 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz,1H), 4.30-4.28 (m, 1H), 3.92 (d, J = 6.1 Hz, 2H), 3.76-3.72 (m, 1H),3.67-3.58 (m, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.47 (s, 3H), 2.33-2.29 (m,1H), 2.18-2.13 (m, 4H), 2.03-2.01 (m, 1H), 1.86-1.83 (m, 2H), 1.65-1.46(m, 6H), 1.40 (s, 9H), 1.35-1.33 (m, 1H), 0.95 (s, 9H) G160

tert-butyl N-[(1S)- 3-carbamoyl-1-[[3- fluoro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 880.45 (400 MHz,DMSO-d₆) δ 10.11 (s, 1H), 8.99 (s, 1H), 8.39 (d, J = 7.7 Hz, 1H), 7.80(d, J = 9.2 Hz, 1H), 7.51- 7.36 (m, 5H), 7.30 (s, 1H), 7.15 (s, 1H),7.09 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.73 (d, J = 9.5 Hz, 1H), 5.11(s, 1H), 4.92-4.85 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0Hz, 1H), 4.29 (s, 1H), 4.01 (q, J = 7.4 Hz, 1H), 3.64-3.59 (m, 2H), 3.35(s, 2H), 2.56-2.54 (m, 2H), 2.46 (s, 3H), 2.24- 2.08 (m, 2H), 2.06-1.70(m, 4H), 1.58-1.48 (m, 4H), 1.39 (s, 9H), 1.37 (s, 2H), 1.28-1.24 (m,3H), 0.93 (s, 9H) G161

tert-butyl N-(4- carbamoyl-1-[[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]amino] butan-2-yl)carbamate 866.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 9.2 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.24 (s, 1H),6.85 (t, J = 7.8 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 6.60(t, J = 8.2 Hz, 1H), 6.41 (t, J = 7.0 Hz, 1H), 5.22 (s, 1H), 5.10(d, J =3.6 Hz, 1H), 4.92 (p, J = 7.5 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43(t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.64-3.56 (m, 6H), 3.12-2.99 (m, 1H),3.06- 3.02 (m, 1H), 2.46 (s, 3H), 2.32-2.20 (m, 3H), 2.17-2.07 (m, 4H),2.09-1.97 (m, 1H), 2.03-1.99 (m, 1H), 1.85- 1.73 (m, 1H), 1.57-1.53 (m,1H), 1.54- 1.50 (m, 5H), 1.39 (d, J = 13.2 Hz, 2H), 1.33-1.21 (m, 6H),0.94 (s, 9H) G162

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)-5- methylphenoxy] butan-2-yl]carbamate 881.40 (300MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 9.2Hz, 1H), 7.40 (q, J = 8.2 Hz, 4H), 7.25 (s, 1H), 6.79 (t, J = 7.5 Hz,2H), 6.72 (s, 1H), 6.59 (dd, J = 6.2, 2.0 Hz, 1H), 5.08 (d, J = 3.6 Hz,1H), 4.97-4.86 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz,1H), 4.28 (s, 1H), 3.88 (d, J = 5.9 Hz, 2H), 3.78-3.66 (m, 1H),3.64-3.57 (m, 2H), 2.45 (s, 3H), 2.33-2.24 (m, 1H), 2.22 (s, 3H),2.17-2.08 (m, 3H), 2.06 (d, J = 0.9 Hz, 3H), 2.05-1.94 (m, 2H),1.87-1.72 (m, 2H), 1.69-1.43 (m, 5H), 1.38 (s, 9H), 1.35 (s, 3H), 0.92(s, 9H) G163

tert-butyl N-[(2S)-4- carbamoyl-1-[2,5- difluoro-3-(5-[[(25)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 885.35 (400 MHz,CD3OD) δ 8.87 (s, 1H), 7.47-7.33 (m, 4H), 6.79-6.70 (m, 1H), 6.59-6.50(m, 1H), 5.00 (q, J = 6.8 Hz, 1H), 4.64-4.53 (m, 2H), 4.43 (br, 1H),3.97 (d, J = 5.4 Hz, 2H), 3.87 (d, J = 10.9 Hz, 2H), 3.74 (dd, J = 11.0,3.9 Hz, 1H), 2.62 (t, J = 7.5 Hz, 2H), 2.47 (s, 3H), 2.39-2.12 (m, 4H),2.04-1.90 (m, 1H), 1.85-1.73 (m, 1H), 1.70-1.54 (m, 5H), 1.50 (d, J =7.0 Hz, 3H), 1.44 (s, 9H), 1.40- 1.35 (m, 3H), 1.03 (s, 9H) G164

(2S,4R)-1-[(2S)-2- (6-[2-[(1S)-3- carbamoyl-1-[(2- methylpropane-2-sulfinyl)amino]propyl] pyridin-4- yl]hexanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]pyrrolidine-2- carboxamide 824.35 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H),840-8.37 (t, J = 6.9 Hz, 2H), 7.81- 7.79 (d, J = 9.3 Hz, 1H), 7.47-7.41(m, 2H), 7.39-7.37 (d, J = 8.3 Hz, 2H), 7.31 (s, 1H), 7.20-7.10 (m, 2H),6.85-6.77(m, 1H), 5.75-5.74 (d, J = 5.5 Hz, 1H), 5.11-5.10 (d, J = 3.5Hz, 1H), 4.96-4.89 (m, 1H), 4.53-4.50 (d, J = 9.4 Hz, 1H), 4.45-4.41 (t,J = 8.0 Hz, 1H), 4.30-4.27 (m, 1H), 4.25- 4.21 (m, 1H), 3.61(s, 1H),2.70-2.67 (t, J = 7.5 Hz, 2H), 2.46 (s, 3H), 2.45-2.23 (m, 1H),2.17-2.01 (m, 3H), 1.91-1.75 (m, 2H), 1.68-1.63 (m, 2H), 1.53-1.51 (m,2H), 1.39-1.37 (d, J = 7.0 Hz, 3H), 1.31-1.23 (m, 2H), 1.20-1.16 (t, J =7.1 Hz, 3H), 1.10 (s, 9H), 0.93 (s, 9H) G165

tert-butyl N-[(2S)-3- carbamoyl-1-[[3-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]carbamoyl] propyl]carbamate 848.65 (300 MHz,DMSO-d₆) δ 9.84 (s, 1H), 8.98 (d, J = 3.6 Hz, 1H), 8.37-8.34 (m, 1H),7.79 (d, J = 9.2 Hz, 1H), 7.43- 7.36 (m, 6H), 7.29-7.17 (m, 2H),7.05-6.69 (m, 3H), 5.08 (s, 1H), 4.96- 4.87 (m, 1H), 4.51 (d, J = 9.5Hz, 1H), 4.45-4.39 (m, 2H), 4.27 (s, 1H), 4.02 (s, 1H), 3.63-3.59 (m,2H), 2.45 (d, J = 3.7 Hz, 3H), 2.28-2.14 (m, 4H), 2.00-1.79 (m, 5H),1.57-1.50 (m, 4H), 1.38-1.30 (m, 12H), 0.93 (s, 9H) G138

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 839.40 (400 MHz,CD3OD) δ 8.91-8.89 (m, 1H), 7.48-7.41 (m, 4H), 7.03-6.93 (m, 2H),6.85-6.82 (m, 1H), 5.03-5.01 (m, 1H), 4.66-4.64 (m, 1H), 4.61- 4.56 (m,1H), 4.47-4.42 (m, 1H), 4.2- 3.99 (m, 2H), 3.90 (d, J = 10.9 Hz, 2H),3.79-3.76 (m, 1H), 2.71-2.67 (m, 2H), 2.50 (s, 3H), 2.34-2.32 (m, 4H),2.24-2.18 (m, 1H), 2.06-1.89 (m, 4H), 1.85-1.81 (m, 1H), 1.53 (d, J =7.0 Hz, 3H), 1.46 (s, 9H), 1.05 (s, 9H) G139

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl)-5- methylphenoxy] butan-2-yl]carbamate 853.40 (300MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 9.2Hz, 1H), 7.40 (q, J = 8.2 Hz, 4H), 7.25 (s, 1H), 6.83-6.76 (m, 2H), 6.72(s, 1H), 6.59 (d, J = 6.1 Hz, 1H), 5.08 (s, 1H), 4.99-4.85 (m, 1H), 4.52(d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 3.88 (d, J= 6.0 Hz, 2H), 3.78-3.66 (m, 1H), 3.64- 3.56 (m, 2H), 2.45 (s, 3H), 2.28(d, J = 6.9 Hz, 1H), 2.23 (s, 3H), 2.20- 2.10 (m, 4H), 2.02-1.95 (m,1H), 1.87-1.67 (m, 5H), 1.66-1.52 (m, 1H), 1.38 (s, 9H), 1.35 (s, 3H),0.94 (s, 9H) G140

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl)-5- methylphenoxy] butan-2-yl]carbamate 867.45 (300MHz, DMSO-d₆) δ 9.00 (d, J = 1.4 Hz, 1H), 8.39 (d, J = 7.7 Hz, 1 H),7.84 (d, J = 9.3 Hz, 1H), 7.50-7.37 (m, 4H), 7.28 (s, 1H), 6.81 (dd, J =20.1, 11.0 Hz, 3H), 6.63 (d, J = 5.9 Hz, 1H), 5.12 (s, 1H), 5.01-4.88(m, 1H), 4.57-4.39 (m, 2H), 4.30 (s, 1H), 3.90 (d, J = 5.9 Hz, 2H),3.79- 3.69 (m, 1H), 3.65-3.58 (m, 2H), 2.47 (s, 3H), 2.25 (s, 3H),2.19-2.12 (m, 3H), 2.09 (d, J = 1.5 Hz, 3H), 2.06- 1.98 (m, 1H),1.88-1.73 (m, 3H), 1.67- 1.58 (m, 1H), 1.56-1.44 (m, 4H), 1.40 (s, 9H),1.37 (s, 3H), 0.95 (s, 9H) G141

tert-butyl N-[(3R)-1- carbamoyl-6-[4-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]hexan-3- yl]carbamate 847.50 ¹H NMR (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 9.2 Hz,1H), 7.48-7.35 (m, 4H), 7.23 (s, 1H), 7.08 (s, 4H), 6.69 (s, 1H), 6.60(d, J = 9.2 Hz, 1H), 5.11 (d, J = 3.6 Hz, 1H), 5.01-4.87 (m, 1H),4.59-4.39 (m, 2H), 4.30 (s, 1H), 3.62 (s, 2H), 3.46-3.38 (m, 1H),2.49-2.47 (m, 2H), 2.46 (s, 3H), 2.36-1.98 (m, 6H), 1.86-1.73 (m, 1H),1.66-1.45 (m, 8H), 1.43-1.24 (m, 15H), 0.95 (s, 9H) G142

tert-butyl N-1(1S)-3- carbamoyl-1-[5-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(lS)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) pyridin-2- yl]propyl]carbamate 820.45 (300 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.42-8.32 (m, 2H), 7.81-7.79 (m, 1H), 7.59-7.56(dd, J = 8.0, 2.3 Hz, 1H), 7.48-7.41 (m, 3H), 7.41-7.32 (m, 2H),7.28-7.23 (m, 1H), 7.21-7.19 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 5.12-5.11 (d, J = 3.6 Hz, 1H), 4.96-4.89 (m, 1H), 4.53-4.50 (d, J = 9.3 Hz,1H), 4.47-4.41 (s, 2H), 4.29-4.27 (m, 1H), 4.06-4.01 (m, 1H), 3.64-3.58(m, 2H), 2.69-2.65 (m, 2H), 2.46 (s, 3H), 2.29-2.22 (m, 1H), 2.15-2.10(m, 1H), 2.06-1.2.02 (m, 3H), 2.00 (s, 1H), 1.93-1.74 (m, 2H), 1.68-1.61(m, 2H), 1.56-1.48 (m, 2H), 1.38 (s, 3H), 1.37-1.35 (m, 7H), 1.27-1.19(m, 3H), 0.93 (s, 9H) G143

tert-butyl N-[(2S)-4- carbamoyl-1-[2- chloro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 855.35 (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 9.2 Hz,1H), 7.45-7.41 (m, 4H), 7.29 (s, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.00 (d,J = 8.3 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H),6.76 (s, 1H), 5.12 (s, 1H), 5.00-4.89 (m, 1H), 4.56 (d, J = 9.2 Hz, 1H),4.45 (t, J = 8.1 Hz, 1H), 4.31 (s, 1H), 3.94 (d, J = 5.9 Hz, 2H), 3.79(s, 1H), 3.64 (s, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.48 (s, 3H), 2.34-2.30(m, 1H), 2.25-2.12 (m, 2H), 2.10 (s, 2H), 1.83- 1.79 (m, 4H), 1.65-1.61(m, 1H), 1.41 (s, 9H), 1.37 (d, J = 11.0 Hz, 3H), 0.97 (s, 9H) G144

tert-butyl N-[(2S)-4- carbamoyl-1-[2- chloro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 869.35 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 9.2 Hz,1H), 7.45 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.30 (d, J =15.6 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91(dd, J = 7.6, 1.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.75 (s, 1H), 5.11(d, J = 3.5 Hz, 1H), 4.99-4.87 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.44(t, J = 8.0 Hz, 1H), 4.31-4.27 (m, 1H), 3.93 (d, J = 6.1 Hz, 2H),3.83-3.73 (m, 1H), 3.67-3.56 (m, 2H), 2.71-2.67 (m, 2H), 2.47 (s, 3H),2.36-2.26 (m, 1H), 2.22-2.10 (m, 3H), 2.10-1.97 (m, 1H), 1.92-1.75 (m,2H), 1.70-1.49 (m, 4H), 1.40 (s, 9H), 1.38-1.34 (m, 2H), 1.31-1.22 (m,2H), 0.94 (s, 9H) G145

tert-butyl N-[(2S)-4- carbamoyl-1-[5- chloro-2-fluoro-3-(5-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 901.35 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.81-7.79 (m, 1H),7.44 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H),7.12-7.10 (m, 1H), 6.92-6.90 (m, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.75 (s,1H), 5.11 (s, 1H), 4.92 (p, J = 7.3 Hz, 1H), 4.53-4.51 (m, 1H), 4.42 (t,J = 8.0 Hz, 1H), 4.29 (s, 1H), 3.97- 3.93 (m, 1H), 3.75-3.73 (m, 1H),3.61 (d, J = 4.1 Hz, 2H), 3.27-3.23 (m, 2H), 2.56 (d, J = 7.6 Hz, 1H),2.46 (s, 3H), 2.31-2.20 (m, 1H), 2.19-2.10 (m, 2H), 2.10-2.06 (m, 2H),2.03- 2.01 (m, 1H), 1.88-1.78 (m, 2H), 1.64- 1.44 (m, 5H), 1.38 (s, 9H),1.27-1.21 (m, 4H), 0.93 (s, 9H) G146

tert-butyl N-(3- carbamoyl-1-[[2- chloro-3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]carbamoyl] propyl)carbamate 882.35 (400 MHz,DMSO-d₆) δ 9.31 (s, 1H), 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1 H), 7.84(d, J = 9.3 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.68-7.53 (m, 1H), 7.44(d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.26 (dd, J = 9.8, 6.6Hz, 2H), 7.13 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 5.10 (d, J = 3.6 Hz,1H), 4.92 (p, J = 7.1Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0Hz, 1H), 4.29 (s, 1H), 4.12 (s, 1H), 3.61 (d, J = 4.2 Hz, 2H), 2.74-2.70(m, 2H), 2.46 (s, 3H), 2.37-2.29 (m, 1H), 2.21- 2.17 (m, 3H), 2.03-1.98(m, 2H), 1.88- 1.74 (m, 2H), 1.58-1.52 (m, 3H), 1.43-1.35 (m, 12H),1.27-1.23 (m, 1H), 0.94 (s, 9H) G147

tert-butyl N-1(1S)-3- carbamoyl-1-[[2- chloro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenyl]carbamoyl] propyl]carbamate 868.35 (400 MHz,DMSO-d₆) δ 9.32 (s, 1H), 8.99 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 7.90(d, J = 9.3 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H),7.38 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 9.6 Hz, 2H), 7.26 (d, J = 8.1 Hz,1H), 7.15-7.08 (m, 1H), 6.81 (s, 1H), 5.10 (s, 1H), 4.92 (p, J = 6.9 Hz,1H), 4.55 (d, J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H),4.13-4.09 (m, 1H), 3.62 (s, 2H), 2.72- 2.68 (m, 2H), 2.46 (s, 3H),2.35-2.31 (m, 1H), 2.23-2.19 (m, 2H), 2.01 (s, 1H), 1.83-1.79 (m, 4H),1.43-1.35 (m, 12H), 1.33-1.23 (m, 2H), 0.95 (s, 9H) G148

tert-butyl N-1(1S)-3- carbamoyl-1-[[3-(3- [[(2S)-1-[(2S,4R)-4-hydroxy-2-II(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenyl]carbamoyl] propyl]carbamate 834.35 (400 MHz,DMSO-d₆) δ 9.96 (s, 1H), 8.99 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.26(s, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 7.9 Hz, 4H), 7.39 (d, J= 8.3 Hz, 2H), 7.33 (d, J = 3.5 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.04(d, J = 7.8 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.80 (s, 1H), 5.76 (s,1H), 4.93 (p, J = 7.2 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.44 (t, J =8.0 Hz, 1H), 4.29 (p, J = 3.2 Hz, 1H), 4.05 (q, J = 7.5 Hz, 1H), 3.63(d, J = 3.2 Hz, 2H), 2.55 (d, J = 2.7 Hz, 1H), 2.46 (s, 3H), 2.29-2.25(m, 1H), 2.18-2.15 (m, 3H), 2.02-1.99 (m, 1H), 1.96-1.86 (m, 1H),1.85-1.71 (m, 4H), 1.38- 1.21 (m, 12H), 0.95 (s, 9H) G149

tert-butyl N-1(1S)-3- carbamoyl-1-[[2- chloro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 896.45 (300 MHz,DMSO-d₆) δ 9.60 (s, 1H), 9.00 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 7.7 Hz,1H), 7.78 (dd, J = 18.0, 8.8 Hz, 2H), 7.43 (q, J = 8.1 Hz, 4H), 7.32 (s,1H), 7.15-7.01 (m, 3H), 6.82 (s, 1H), 5.12 (d, J = 3.5 Hz, 1H), 4.95 (t,J = 7.3Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.45 (t, J = 8.0 Hz, 1H),4.36-4.24 (m, 1H), 4.20-4.15 (m, 1H), 3.63 (s, 2H), 3.36 (d, J = 1.2 Hz,2H), 2.61 (t, J = 7.7 Hz, 2H), 2.48 (s, 3H), 2.31-2.11 (m, 3H),2.10-1.88 (m, 1H), 1.88-1.71 (m, 2H), 1.63-1.48 (m, 2H), 1.46-1.22 (m,14H), 0.95 (s, 9H) G150

tert-butyl N-1(1S)-3- carbamoyl-1-[[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 880.09 (300 MHz,DMSO-d₆) δ 9.32 (s, 1H), 9.00 (d, J = 1.3 Hz, 1H), 8.39 (d, J = 7.7 Hz,1H), 7.78 (dd, J = 18.1,8.6 Hz, 2H), 7.49-7.36 (m, 5H), 7.32- 7.25 (m,2H), 7.14 (d, J = 7.5 Hz, 1H), 6.82 (s, 1H), 5.12 (s, 1H), 5.01-4.86 (m,1H), 4.54 (d, J = 9.1 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.30 (s, 1H),4.17-4.11 (m, 1H), 2.71 (t, J = 7.8 Hz, 2H), 2.48 (s, 3H), 2.34-2.12 (m,3H), 2.07-1.96 (m, 1H), 1.86-1.77 (m, 2H), 1.62-1.50 (m, 4H), 1.46-1.20(m, 18H), 0.95 (s, 9H) G151

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 4- methylphenoxy] butan-2-yl]carbamate 881.40 (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.45-7.31 (m, 2H), 7.27 (s, 1H),6.92-6.85 (m, 2H), 6.82 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 5.10 (d, J =3.6 Hz, 1H), 4.92 (p, J = 7.3 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43(t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.89-3.85 (m, 2H), 3.75-3.68 (m, 1H),3.61 (d, J = 4.1 Hz, 2H), 2.58-2.54 (m, 2H), 2.46 (s, 3H), 2.34-2.23 (m,1H), 2.21 (s, 3H), 2.17-2.06 (m, 3H), 2.05- 1.97 (m, 2H), 1.88-1.74 (m,2H), 1.64- 1.44 (m, 5H), 1.38 (s, 9H), 1.36-1.14 (m, 4H), 0.93 (s, 9H)G152

tert-butyl N-[(2S)-4- carbamoyl-1-[2,4- difluoro-3-(5[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 885.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 9.3 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.45-7.31 (m, 2H), 7.27 (s, 1H),7.05-7.01 (m, 1H), 6.97-6.95 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.74 (s,1H), 5.10 (d, J = 3.5 Hz, 1H), 4.92 (p, J = 7.0 Hz, 1H), 4.51 (d, J =9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.90 (d, J = 6.0Hz, 2H), 3.76-3.67 (m, 1H), 3.66-3.55 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H),2.46 (s, 3H), 2.32-2.20 (m, 1H), 2.17-2.06 (m, 3H), 2.04-1.98 (m, 1H),1.86-1.74 (m, 2H), 1.64-1.43 (m, 5H), 1.39 (s, 9H), 1.35-1.20 (m, 4H),1.10-1.02 (m, 1H), 0.93 (s, 9H) G153

tert-butyl N-[(2S)-4- carbamoyl-1-[3- ([[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]methyl) phenoxy]butan-2- yl]carbamate 793.30 (400 MHz,DMSO-d₆) δ 8.99 (s, 1 H), 8.40 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 9.2 Hz,1H), 7.48-7.31 (m, 4H), 7.28 (s, 1H), 7.19 (t, J = 7.9 Hz, 1H), 8.99 (s,1H), 6.94-6.67 (m, 5H), 5.11 (d, J = 3.5 Hz, 1H), 4.99-4.87 (m, 1H),4.52-4.39 (m, 2H), 4.30-4.24 (m, 1H), 3.90-3.67 (m, 3H), 3.66- 3.54 (m,3H), 3.40 (d, J = 13.7 Hz, 1H), 2.46 (s, 3H), 2.18-2.09 (m, 6.4 Hz, 2H),2.03-1.99 (m, 1H), 1.83-1.70 (m, 2H), 1.68-1.54 (m, 1H), 1.42-1.38 (m,10H), 1.38-1.36 (s, 2H), 0.92 (s, 9H) G154

tert-butyl N-1(1S)-3- carbamoyl-1-[[3- chloro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 896.45 (300 MHz,DMSO-d₆) δ 10.07 (s, 1H), 8.97 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.77(d, J = 9.2 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.40 (q, J = 8.3 Hz, 4H),7.28 (s, 2H), 7.06 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 1.7 Hz, 1H), 6.77(s, 1H), 5.09 (d, J = 3.5 Hz, 1H), 4.97-4.86 (m, 1H), 4.51 (d, J = 9.3Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.00 (d, J = 6.9 Hz,1H), 3.60 (s, 2H), 2.53 (d, J = 7.5 Hz, 2H), 2.45 (s, 3H), 2.30-2.10 (m,4H), 2.01-1.74 (m, 4H), 1.65-1.42 (m, 4H), 1.41-1.35 (m, 11H), 1.33-1.19(m, 4H), 0.92 (s, 9H) G155

tert-butyl N-[(1S)-3- carbamoyl-1-[[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 5-methylphenyl] carbamoyl]propyl] carbamate 876.40(300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.00 (s, 1H), 8.37 (d, J = 7.7 Hz,1H), 7.79 (d, J = 9.2 Hz, 1H), 7.49- 7.38 (m, 4H), 7.29-7.18 (m, 3H),7.00 (d, J = 7.8 Hz, 1H), 6.79-6.72 (m, 2H), 5.10 (d, J = 3.5 Hz, 1H),5.01- 4.83 (m, 1H), 4.63-4.36 (m, 2H), 4.30 (s, 1H), 4.06-3.97 (m, 1H),3.62 (d, J = 3.2 Hz, 2H), 3.04-2.45 (m, 6H), 2.26 (s, 3H), 2.18-2.13 (m,6H), 1.95- 1.70 (m, 2H), 1.62-1.51 (m, 4H), 1.39 (s, 9H), 1.32-1.24 (m,4H), 0.95 (s, 9H) G156

tert-butyl N-1(1S)-3- carbamoyl-1-[[3-(5- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(lS)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 2-methylphenyl] carbamoyl]propyl] carbamate 876.50(300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.00 (s, 1H), 8.40 (d, J = 7.7 Hz,1H), 7.82 (d, J = 92 Hz, 1H), 7.47-7.34 (m, 6H), 7.23-6.93 (m, 4H), 6.82(s, 1H), 5.13(d, J = 3.5Hz, 1H), 4.96- 4.90 (m, 1H), 4.60-4.38 (m, 2H),4.30 (s, 1H), 4.08 (d, J = 6.8 Hz, 1H), 3.63 (d, J = 3.3 Hz, 2H), 2.60(d, J = 7.6 Hz, 2H), 2.47 (s, 3H), 2.36-1.88 (m, 9H), 1.85-1.81 (m, 2H),1.67-1.46 (m, 4H), 1.41 (d, J = 3.8 Hz, 11H), 1.39-1.14 (m, 2H), 0.95(s, 9H) G157

tert-butyl N-[(2S)-4- carbamoyl-1-[3-(2- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]ethyl) phenoxy]butan-2- yl]carbamate 807.3 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 9.3 Hz,1H), 7.44 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.28 (s, 1H),7.16 (t, J = 7.8 Hz, 1H), 6.86- 6.70 (m, 5H), 5.76 (s, 1H), 5.17-5.09(m, 1H), 4.93 (p, J = 7.2 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.44 (t, J= 8.0 Hz, 1H), 4.29 (s, 1H), 3.84 (qd, J = 9.6, 5.8 Hz, 2H), 3.72 (dp, J= 9.0, 4.9 Hz, 1H), 3.62 (d, J = 3.4 Hz, 2H), 3.35-3.32 (m, 4H),2.85-2.69 (m, 2H), 2.60-2.58 (m, 1H), 2.46 (s, 3H), 2.20-1.99 (m, 4H),1.82-1.76 (m, 2H), 1.62-1.57 (m, 1H), 1.44 (s, 9H), 0.90 (s, 9H) G158

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 839.40 (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 9.2 Hz,1H), 7.42 (q, J = 8.3 Hz, 4H), 7.29 (s, 1H), 7.03-6.98 (m, 2H),6.84-6.80 (m, 2H), 6.74 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 4.98-4.88 (m,1H), 4.54 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H),3.93 (d, J = 6.0 Hz, 2H), 3.75-3.73 (m, 1H), 3.64-3.61 (m, 2H), 2.58 (t,J = 7.6 Hz, 2H), 2.47 (s, 3H), 2.32- 2.28 (m, 1H), 2.21-2.16 (m, 2H),2.07- 1.97 (m, 1H), 1.87-1.69 (m, 5H), 1.64-1.62 (m, 1H), 1.40 (s, 9H),0.96 (s, 9H) G159

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenoxy]butan-2- yl]carbamate 853.35 (400 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 9.3 Hz,1H), 7.45 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H),7.06-6.96 (m, 2H), 6.87-6.80 (m, 2H), 6.75 (s, 1H), 5.11 (d, J = 3.5 Hz,1H), 4.94-4.92 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz,1H), 4.30-4.28 (m, 1H), 3.92 (d, J = 6.1 Hz, 2H), 3.76-3.72 (m, 1H),3.67-3.58 (m, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.47 (s, 3H), 2.33-2.29 (m,1H), 2.18-2.13 (m, 4H), 2.03-2.01 (m, 1H), 1.86-1.83 (m, 2H), 1.65-1.46(m, 6H), 1.40 (s, 9H), 1.35-1.33 (m, 1H), 0.95 (s, 9H) G160

tert-butyl N-[(1S)- 3-carbamoyl-1-[[3- fluoro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl] propyl]carbamate 880.45 (400 MHz,DMSO-d₆) δ 10.11 (s, 1H), 8.99 (s, 1H), 8.39 (d, J = 7.7 Hz, 1H), 7.80(d, J = 9.2 Hz, 1H), 7.51- 7.36 (m, 5H), 7.30 (s, 1H), 7.15 (s, 1H),7.09 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.73 (d, J = 9.5 Hz, 1H), 5.11(s, 1H), 4.92-4.85 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0Hz, 1H), 4.29 (s, 1H), 4.01 (q, J = 7.4 Hz, 1H), 3.64-3.59 (m, 2H), 3.35(s, 2H), 2.56-2.54 (m, 2H), 2.46 (s, 3H), 2.24- 2.08 (m, 2H), 2.06-1.70(m, 4H), 1.58-1.48 (m, 4H), 1.39 (s, 9H), 1.37 (s, 2H), 1.28-1.24 (m,3H), 0.93 (s, 9H) G161

tert-butyl N-(4- carbamoyl-1-[[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]amino] butan-2-yl)carbamate 866.40 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 9.2 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.24 (s, 1H),6.85 (t, J = 7.8 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 6.60(t, J = 8.2 Hz, 1H), 6.41 (t, J = 7.0 Hz, 1H), 5.22 (s, 1H), 5.10(d, J =3.6 Hz, 1H), 4.92 (p, J = 7.5 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43(t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.64-3.56 (m, 6H), 3.12-2.99 (m, 1H),3.06- 3.02 (m, 1H), 2.46 (s, 3H), 2.32-2.20 (m, 3H), 2.17-2.07 (m, 4H),2.09-1.97 (m, 1H), 2.03-1.99 (m, 1H), 1.85- 1.73 (m, 1H), 1.57-1.53 (m,1H), 1.54- 1.50 (m, 5H), 1.39 (d, J = 13.2 Hz, 2H), 1.33-1.21 (m, 6H),0.94 (s, 9H) G162

tert-butyl N-[(2S)-4- carbamoyl-1-[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) 5-methylphenoxy] butan-2-yl]carbamate 881.40 ¹H NMR(300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.77 (d, J= 9.2 Hz, 1H), 7.40 (q, J = 8.2 Hz, 4H), 7.25 (s, 1H), 6.79 (t, J = 7.5Hz, 2H), 6.72 (s, 1H), 6.59 (d d, J = 6.2, 2.0 Hz, 1H), 5.08 (d, J = 3.6Hz, 1H), 4.97-4.86 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0Hz, 1H), 4.28 (s, 1H), 3.88 (d, J = 5.9 Hz, 2H), 3.78-3.66 (m, 1H),3.64- 3.57 (m, 2H), 2.45 (s, 3H), 2.33-2.24 (m, 1H), 2.22 (s, 3H),2.17-2.08 (m, 3H), 2.06 (d, J = 0.9 Hz, 3H), 2.05- 1.94 (m, 2H),1.87-1.72 (m, 2H), 1.69- 1.43 (m, 5H), 1.38 (s, 9H), 1.35 (s, 3H), 0.92(s, 9H) G163

tert-butyl N-[(2S)-4- carbamoyl-1-[2,5- difluoro-3-(5-[[(25)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamate 885.35 ¹H NMR (400MHz, CD3OD) δ 8.87 (s, 1H), 7.47-7.33 (m, 4H), 6.79- 6.70 (m, 1H),6.59-6.50 (m, 1H), 5.00 (q, J = 6.8 Hz, 1H), 4.64-4.53 (m, 2H), 4.43(br, 1H), 3.97 (d, J = 5.4 Hz, 2H), 3.87 (d, J = 10.9 Hz, 2H), 3.74 (dd,J = 11.0, 3.9 Hz, 1H), 2.62 (t, J = 7.5 Hz, 2H), 2.47 (s, 3H), 2.39-2.12 (m, 4H), 2.04-1.90 (m, 1H), 1.85- 1.73 (m, 1H), 1.70-1.54 (m, 5H),1.50 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H), 1.40-1.35 (m, 3H), 1.03 (s, 9H)G164

(2S,4R)-1-[(2S)-2- (6-[2-[(1S)-3- carbamoyl-1-[(2- methylpropane-2-sulfinyl)amino] propyl]pyridin-4- yl]hexanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]pyrrolidine-2- carboxamide 824.35 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H),840-8.37 (t, J = 6.9 Hz, 2H), 7.81- 7.79 (d, J = 9.3 Hz, 1H), 7.47-7.41(m, 2H), 7.39-7.37 (d, J = 8.3 Hz, 2H), 7.31 (s, 1H), 7.20-7.10 (m, 2H),6.85-6.77(m, 1H), 5.75-5.74 (d, J = 5.5 Hz, 1H), 5.11-5.10 (d, J = 3.5Hz, 1H), 4.96-4.89 (m, 1H), 4.53-4.50 (d, J = 9.4 Hz, 1H), 4.45-4.41 (t,J = 8.0 Hz, 1H), 4.30-4.27 (m, 1H), 4.25- 4.21 (m, 1H), 3.61(s, 1H),2.70-2.67 (t, J = 7.5 Hz, 2H), 2.46 (s, 3H), 2.45-2.23 (m, 1H),2.17-2.01 (m, 3H), 1.91-1.75 (m, 2H), 1.68-1.63 (m, 2H), 1.53-1.51 (m,2H), 1.39-1.37 (d, J = 7.0 Hz, 3H), 1.31-1.23 (m, 2H), 1.20-1.16 (t, J =7.1 Hz, 3H), 1.10 (s, 9H), 0.93 (s, 9H) G165

tert-butyl N-1(1S)-3- carbamoyl-1-[[3-(4- [[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(15)-1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]carbamoyl] propyl]carbamate 848.65 (300 MHz,DMSO-d₆) δ 9.84 (s, 1H), 8.98 (d, J = 3.6 Hz, 1H), 8.37-8.34 (m, 1H),7.79 (d, J = 9.2 Hz, 1H), 7.43- 7.36 (m, 6H), 7.29-7.17 (m, 2H),7.05-6.69 (m, 3H), 5.08 (s, 1H), 4.96- 4.87 (m, 1H), 4.51 (d, J = 9.5Hz, 1H), 4.45-4.39 (m, 2H), 4.27 (s, 1H), 4.02 (s, 1H), 3.63-3.59 (m,2H), 2.45 (d, J = 3.7 Hz, 3H), 2.28-2.14 (m, 4H), 2.00-1.79 (m, 5H),1.57-1.50 (m, 4H), 1.38-1.30 (m, 12H), 0.93 (s, 9H) G168

tert-butyl N-[(2S)-4- carbamoyl-1-[2- chloro-3-(3-[[(25)-1-[(2S,4R)-4-hydroxy- 2-([1-[4-(4-methyl- l,3-thiazol-5-yl)phenyl]cyclopropyl] carbamoyl)pyrrolidin- 1-yl]-3,3- dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 867.20(400 MHz, Methanol-d₄) δ 8.88 (d, J = 2.6 Hz, 1H), 7.43-7.32 (m, 4H),7.22- 7.16 (m, 1H), 6.99-6.91 (m, 2H), 4.67-4.51 (m, 3H), 4.04-3.91 (m,3H), 3.85-3.80 (m, 1H), 2.84-2.76 (m, 2H), 2.52-2.45 (m, 3H), 2.45-2.33(m, 4H), 2.26-2.18 (m, 1H), 2.10-2.02 (m, 3H), 1.98-1.81 (m, 3H), 1.50-1.42 (m, 9H), 1.40-1.28 (m, 4H), 1.07 (s, 9H) G169

tert-butyl N-[(2S)- 4-carbamoyl-1-[2- chloro-5-fluoro-3-(3-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 873.30 (300 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.39 (d, J = 7.8Hz, 1H), 7.91 (d, J = 9.3 Hz,1H), 7.42-7.78 (m, 4H), 7.28 (s, 1H), 6.98 (d, J = 10.3 Hz, 1H),6.87-6.73 (m, 3H), 5.11 (d, J = 3.5 Hz, 1H), 4.99-4.90 (m, 1H), 4.54 (d,J = 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.30-4.28 (m, 1H), 4.01-3.91(m, 2H), 3.79-3.75 (m, 1H), 2.68 (t, J = 7.6 Hz, 2H), 2.47 (s, 3H),2.30- 2.16 (m, 4H), 2.07-1.95 (m, 1H), 1.89-1.79 (m, 6H), 1.65-1.62 (m,1H), 1.39 (s, 9H), 1.34-1.32 (m, 3H), 0.96 (s, 9H) G170

tert-butyl N-[(2S)-4- carbamoyl-1-[2,5- difluoro-3-(3-[[(25)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamate 857.30 (300 MHz,DMSO-d₆) δ 9.00 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 7.7 Hz, 1H), 7.90 (d,J = 9.3 Hz, 1H), 7.42 (q, J = 8.2 Hz, 4H), 7.29 (s, 1H), 6.98 (s, 1H),6.87 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 5.12-5.10 (m, 1H),5.02-4.88 (m, 1H), 4.54 (d, J = 9.0 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H),4.30-4.28 (m, 1H), 3.95-3.91 (m, 2H), 3.75-3.72 (m, 1H), 3.63-3.61 (m,2H), 2.59-2.57 (m, 2H), 2.47 (s, 3H), 2.28-2.25 (m, 3H), 2.17-2.11 (m,2H), 1.77-1.71 (m, 5H), 1.39-1.36 (m, 12H), 0.96 (s, 9H) G171

tert-butyl N-[(2S)-4- carbamoyl-1-[2- chloro-3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl)-5- methylphenoxy] butan-2-yl]carbamate 869.35 (300MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 9.2Hz, 1H), 7.42 (q, J = 8.4 Hz, 4H), 7.28 (s, 1H), 6.87-6.67 (m, 4H), 5.11(d, J = 3.5 Hz, 1H), 4.98-4.88 (m, 1H), 4.55 (d, J = 9.3 Hz, 1H), 4.44(t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 3.91 (d, J = 6.1 Hz, 2H), 3.82-3.74(m, 1H), 3.63 (d, J = 3.3 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 2.47 (s,3H), 2.36- 2.23 (m, 5H), 2.22-2.10 (m, 2H), 2.07-1.97 (m, 1H), 1.93-1.68(m, 4 H), 1.66-1.55 (m, 1H), 1.40-1.37 (m, 12H), 0.96 (s, 9H)

Tert-butylN-[(3S,4R)-1-carbamoyl-4-([4-[3-([[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]amino)propyl]phenyl]methoxy)pentan-3-yl]carbamate(Intermediate G113)

To a stirred solution of tert-butylN-[(3S,4R)-4-[[4-(3-aminopropyl)phenyl]methoxy]-1-carbamoylpentan-3-yl]carbamate(1.31 g, 3.329 mmol) and TEA (1.01 g, 9.987 mmol) in DCM (10.00 mL) wasadded triphosgene (345.74 mg, 1.165 mmol) in portions at 0° C. undernitrogen atmosphere. The resulting mixture was stirred for 2 h at 0° C.under nitrogen atmosphere. To the above mixture was added(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(1.44 g, 3.335 mmol) in portions at 0° C. The resulting mixture wasstirred for additional 2 h at room temperature. The resulting mixturewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with CH₂Cl₂/MeOH (12:1) toafford the title compound as a yellow solid (1.15 g, 41%): ¹H NMR (400MHz, CDCl₃) δ 8.70 (s, 1H), 7.67 (s, 1H), 7.34 (d, J=1.3 Hz, 3H), 7.21(t, J=6.9 Hz, 4H), 7.14 (dd, J=12.2, 7.8 Hz, 4H), 6.45 (d, J=27.0 Hz,2H), 4.90 (d, J=9.5 Hz, 2H), 4.56 (dd, J=11.6, 3.9 Hz, 2H), 4.39-4.28(m, 3H), 3.57-3.52 (m, 5H), 2.65-2.60 (m, 4H), 2.51 (s, 3H), 2.26-2.20(m, 2H), 2.09-1.89 (m, 2H), 1.81-1.77 (m, 2H), 1.60-1.56 (m, 2H), 1.43(s, 9H), 1.19 (s, 3H), 0.95 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=850.65.

4-[3-([2-[(tert-Butoxycarbonyl)amino]-4-carbamoylbutyl](methyl)amino)-2-fluorophenyl]butyl4-nitrophenyl carbonate (Intermediate G166)

4-[3-([2-[(tert-butoxycarbonyl)amino]-4-carbamoylbutyl](methyl)amino)-2-fluorophenyl]butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate.To a stirred solution of tert-butylN-(4-carbamoyl-1-[[2-fluoro-3-(4-hydroxybutyl)phenyl](methyl)amino]butan-2-yl)carbamate(693 mg, 1.69 mmol) and pyridine (200 mg, 2.53 mmol) in THF (10 mL) wasadded 4-nitrophenyl carbonochloridate (374 mg, 1.85 mmol) in THF (10 mL)dropwise at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 2 h at room temperature under nitrogen atmosphere until theactive ester was fully converted. The reaction mixture was quenched withSat.aq. NaHCO₃ (20 mL) and extracted with EA (20 mL). The organic layerwas washed with brine (10 mL), dried over anhydrous Na₂SO₄ and filtered.The filtrate was concentrated under vacuum to give crude4-[3-([2-[(tert-butoxycarbonyl)amino]-4-carbamoylbutyl](methyl)amino)-2-fluorophenyl]butyl4-nitrophenyl carbonate intermediate. The crude intermediate wasre-dissolved in THF (10 mL). Then to above solution were added(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamidehydrochloride (972 mg, 2.02 mmol), TEA (340 mg, 3.37 mmol) and DMA (5mL) at room temperature under nitrogen atmosphere. The resulting mixturewas stirred for 2 h at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure and theresidue was purified by reverse phase flash chromatography with thefollowing conditions: column, Spherical C18 Column, 20-40 um, 330 g;Mobile Phase A: Water (plus 10 mmol/L NH₄HCO₃), Mobile Phase B: ACN;Gradient: 40% to 60% B in 20 min; Detector: UV 254/220 nm. Desiredfractions were collected at 53% B, concentrated under reduced pressureand lyophilized to afford title compound (852 mg, 57.36%) as a whitesolid; ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J=7.7 Hz, 1H),7.41 (d, J=17.1 Hz, 4H), 7.22 (s, 1H), 6.94 (t, J=7.7 Hz, 2H), 6.79 (t,J=8.2 Hz, 1H), 6.73 (t, J=6.8 Hz, 1H), 6.69 (s, 1H), 6.55 (d, J=9.1 Hz,1H), 5.11 (s, 1H), 4.95-4.87 (m, 1H), 4.44 (t, J=8.0 Hz, 1H), 4.29 (s,1H), 4.18 (d, J=9.1 Hz, 1H), 4.01 (s, 1H), 3.95 (s, 1H), 3.62-3.58 (m,2H), 3.08-3.02 (m, 2H), 2.79 (d, J=4.0 Hz, 3H), 2.60-2.56 (m, 3H), 2.46(s, 3H), 2.08-1.94 (m, 4H), 1.84-1.73 (m, 2H), 1.63-1.57 (m, 4H),1.46-1.42 (m, 1H), 1.37 (s, 9H), 1.34-1.30 (m, 2H), 0.94 (s, 9H); LC/MS(ESI, m/z): [(M+1]⁺=882.35

The intermediates in Table 48 were prepared according to the procedureto prepare Intermediate G166.

TABLE 48 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMR G167625

4-[3-[(2S)-2-[(tert- butoxycar- bonyl)amino]-4- carbamoylbutoxy]-2-fluorophenyl]butyl N-[(2S)-1- [(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamate 869.60 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.47-7.42 (m, 2H),7.38 (d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 7.06-6.97 (m, 2H), 6.99- 6.91(m, 1H), 6.83 (td, J = 6.6, 2.5 Hz, 2H), 6.74 (s, 1H), 5.11 (s, 1H),4.91 (p, J = 7.0 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.17(d, J = 9.2 Hz, 1H), 4.00 (s, 1H), 3.92 (d, J = 6.0 Hz, 3H), 3.74 (s,1H), 3.62-3.58 (m, 2H), 2.63-2.59 (m, 1H), 2.46 (s, 3H), 2.15-2.11 (m,2H), 2.08- 1.97 (m, 1H), 1.81-1.77 (m, 2H), 1.58 (s, 5H), 1.39 (s, 9H),1.33 (s, 2H), 1.25 (s, 2H), 0.94 (s, 9H)

(4S,5R)-4-amino-5-([4- [3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)hexanamidehydrochloride (Intermediate H)

To a solution of tert-butylN-[(3S,4R)-1-carbamoyl-4-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)pentan-3-yl]carbamate(400 mg, 0.54 mmol) in 1,4-dioxane (6.00 mL) was added HCl (4 Min1,4-dioxane, 6.00 mL) at 0° C. under nitrogen atmosphere. The resultingmixture was stirred for 5 hours at room temperature. The resultingmixture was concentrated under reduced pressure to afford the titlecompound as a brown solid (350 mg, 96%): ¹H NMR (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.73-7.66 (m, 1H), 7.43 (s, 1H), 7.29 (d, J=8.0 Hz, 2H),7.18 (d, J=7.9 Hz, 2H), 7.05-6.99 (m, 2H), 6.90-6.84 (m, 2H), 5.34 (dd,J=12.9, 5.2 Hz, 1H), 4.53 (d, J=11.8 Hz, 1H), 4.45 (d, J=11.7 Hz, 1H),4.22 (d, J=6.5 Hz, 1H), 3.75 (dd, J=6.2, 3.4 Hz, 1H), 3.52-3.48 (m, 7H),3.34-3.29 (m, 4H), 2.68-2.60 (m, 5H), 2.27-2.21 (m, 2H), 2.04-1.95 (m,2H), 1.81-1.73 (m, 6H), 1.69-1.59 (m, 2H), 1.28-1.21 (m, 3H), 1.15 (d,J=6.6 Hz, 2H); MS (ESI, m/z): [(M+1)]⁺=638.40.

The following intermediates in Table 49 were prepared according to theabove procedure to prepare Intermediate H.

TABLE 49 Characterization data for intermediates prepared according toprocedure above. MS: Intermediate Structure Chemical Name [(M + 1)]⁺¹H-NMR H1

(4S,5R)-4-amino-5- [[4-(3-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-4- yl]propoxylpro- pyl)phenyl]meth- oxy]hexanamidehydrochloride 594.4 (400 MHz, CD₃OD) δ 7.32 (d, J = 8.0 Hz, 2H),7.29-7.16 (m, 2H), 7.09-7.02 (m, 1H), 6.98 (td, J = 8.4, 7.5, 1.4 Hz,2H), 5.34 (dd, J = 12.3, 5.4 Hz, 1H), 4.64 (d, J = 11.6 Hz, 1H),4.56-4.44 (m, 1H), 3.89-3.75 (m, 1H), 3.77 (s, 1H), 3.70-3.66 (m, 8H),3.61 (s, 1H), 3.52-3.46 (m, 4H), 3.38 (dt, J = 8.3, 4.3 Hz, 1H),3.13-3.04 (m, 2H), 2.97-2.87 (m, 1H), 2.87-2.74 (m, 2H), 2.71 (t, J =7.6 Hz, 2H), 2.44 (dt, J = 11.3, 7.2 Hz, 1H), 2.00-1.90 (m, 1H), 1.92(s, 3H), 1.93-1.81 (m, 2H), 1.25 (d, J = 6.5 Hz, 3H). H2

(4S,5R)-4-amino-5- [[4-[3-(2-[3-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]propoxy]eth- oxy)pro-pyl]phenyl]meth- oxy)hexanamide hydrochloride 638.5 (400 MHz, CD₃OD) δ7.46-7.14 (m, 4H), 7.03-6.87 (m, 3H), 5.33 (s, 1H), 4.61 (d, J = 11.5Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.22 (s, 1H), 3.77 (s, 4H), 3.62 (s,9H), 3.09 (s, 2H), 2.92 (d, J = 14.0 Hz, 2H), 2.80 (d, J = 14.8 Hz, 2H),2.71 (s, 2H), 2.42 (s, 2H), 2.16 (s, 2H), 1.60 (s, 1H), 1.42 (s, 1H),1.24 (d, J = 6.3 Hz, 3H). H3

(4S,5R)-4-amino-5- ([4-[3-(2-[3-[3- methyl-1-(1- methyl-2,6-dioxopiperidin-3- yl)-2-oxo-1,3- benzodiazol-4- yl]propoxy]eth- oxy)pro-pyl]phenyl]meth- oxy)hexanamide hydrochloride 652.5 (400 MHz, CD₃OD) δ7.30 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.4 Hz, 2H), 7.09-6.92 (m, 3H),5.35 (dd, J = 13.0, 5.2 Hz, 1H), 4.85 (s, 2H), 3.83-3.74 (m, 2H),3.70-3.62 (m, 4H), 3.63 (d, J = 14.5 Hz, 4H), 3.63-3.55 (m, 2H),3.58-3.46 (m, 2H), 3.19 (d, J = 5.5 Hz, 2H), 3.09 (t, J = 7.7 Hz, 2H),2.94 (s, 1H), 2.75 (dt, J = 32.0, 6.6 Hz, 2H), 1.97- 1.84 (m, 6H), 1.41(d, J = 4.8 Hz, 4H), 1.33-1.20 (m, 4H). H4

(4S,5R)-4-amino-5- ([4-[3-(3-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]propoxylpro- poxy)pro-pyl]phenyl]meth- oxy)hexanamide hydrochloride 652.4 (400 MHz, CDCl₃) δ8.73 (s, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H),6.94-6.86 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.81-4.78 (m, 1H),4.45-4.42 (m, 1H), 4.33 (t, J = 4.7 Hz, 2H), 4.26-4.21 (m, 1H),3.92-3.88 (m, 4H), 3.81 (s, 5H), 3.58-3.53 (m, 4H), 3.47-3.41 (m, 3H),2.80-2.54 (m, 7H), 1.88 (s, 5H), 1.27 (s, 3H). H5

(4S,5R)-4-amino-5- ([4-[3-(3-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]propoxy]pro- poxy)pro-pyl]phenyl]meth- oxy)hexanamide hydrochloride 652.5 (400 MHz, CD₃OD) δ7.33-7.21 (m, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.05 (t, J = 7.8 Hz, 1H),6.98 (t, J = 8.2 Hz, 2H), 5.34 (dd, J = 12.3, 5.4 Hz, 1H), 4.70-4.54 (m,1H), 4.53-4.44 (m, 1H), 3.89-3.75 (m, 2H), 3.68- 3.62 (m, 3H), 3.67-3.52(m, 4H), 3.44 (t, J = 6.4 Hz, 2H), 3.33 (s, 4H), 3.07 (t, J = 7.9 Hz,2H), 2.96-2.87 (m, 1H), 2.81 (d, J = 14.0 Hz, 2H), 2.70 (t, J = 7.7 Hz,2H), 2.43 (dt, J = 11.6, 7.4 Hz, 1H), 1.93-1.86 (m, 8H), 1.23-1.19 (m,3H). H6

(4S,5R)-4-amino-5- ([4-[3-(4-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]propoxy]bu- toxy)pro-pyl]phenyl]meth- oxy)hexanamide hydrochloride 666.5 (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.87 (d, J = 45.3 Hz, 2H), 7.31-7.27 (m, 1H), 7.20-7.16(m, 2H), 7.07 (s, 1H), 7.02 (d, J = 14.9 Hz, 2H), 6.87 (d, J = 8.1 Hz,1H), 5.76 (s, 1H), 5.34 (dd, J = 12.8, 5.3 Hz, 1H), 4.57-4.41 (m, 2H),4.12 (dd, J = 11.0, 6.0 Hz, 1H), 4.07-3.99 (m, 1H), 3.87 (s, 2H),3.78-3.72 (m, 2H), 3.40 (s, 6H), 2.70- 2.55 (m, 5H), 2.27-2.17 (m, 2H),2.08 (s, 2H), 2.01 (d, J = 8.1 Hz, 1H), 1.92 (s, 1H), 1.79 (dq, J =15.2, 7.7 Hz, 5H), 1.60-1.50 (m, 4H), 1.36 (s, 1H), 1.24 (s, 1H), 1.16-1.07 (m, 3H). H7

(4S,5R)-4-amino-5- ([4-[3-(4-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]propoxy]bu- toxy)pro-pyl]phenyl]meth- oxy)hexanamide hydrochloride 666.4 (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.02 (s, 2H), 7.45 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H),7.29 (d, J = 7.8 Hz, 2H), 7.26-7.09 (m, 3H), 6.97 (d, J = 5.8 Hz, 2H),6.96-6.83 (m, 2H), 5.38 (dd, J = 12.5, 5.4 Hz, 1H), 4.52 (d, J = 11.6Hz, 1H), 4.48-4.34 (m, 1H), 4.16-4.06 (m, 1H), 3.80-3.72 (m, 1H),3.53-3.46 (m, 1H), 3.44 (d, J = 5.3 Hz, 1H), 3.41 (s, 5H), 3.40 (s, 4H),3.39-3.31 (m, 2H), 3.26 (s, 1H), 2.96 (t, J = 7.9 Hz, 2H), 2.29-2.17 (m,2H), 2.00 (dd, J = 11.8, 4.8 Hz, 2H), 1.78 (tt, J = 21.4, 8.1 Hz, 6H),1.36 (s, 3H), 1.22-1.06 (m, 4H). H8

(4S,5R)-4-amino-5- [(4-[3-[(6-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]propoxy]hex- yl)oxy]pro-pyl]phenyl)meth- oxy]hexanamide hydrochloride 680.4 (400 MHz, CD₃OD) δ7.28 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.3 Hz,2H), 6.98 (d, J = 8.1 Hz, 1H), 5.32 (dd, J = 12.6, 5.5 Hz, 1H), 4.62 (d,J = 11.5 Hz, 1H), 4.50 (d, J = 11.5 Hz, 1H), 4.23 (d, J = 6.6 Hz, 1H),3.84-3.73 (m, 3H), 3.68 (d, J = 1.1 Hz, 11H), 2.92 (dd, J = 18.3, 5.2Hz, 1H), 2.79 (q, J = 9.9, 8.1 Hz, 4H), 2.68 (t, J = 7.7 Hz, 2H),2.51-2.35 (m, 2H), 2.17 (d, J = 10.5 Hz, 1H), 1.89 (dp, J = 21.9, 6.9Hz, 2H), 1.63 (q, J = 6.9 Hz, 5H), 1.52 (s, 2H), 1.31 (s, 1H), 1.24 (d,J = 6.4 Hz, 3H). H9

(4S,5R)-4-amino-5- [(4-[3-[(5-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]pro- poxy]pentyl)oxy]pro-pyl]phenyl)meth- oxy]hexanamide hydrochloride 680.5 (400 MHz, CD₃OD) δ7.29 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.09-6.93 (m, 3H),5.34 (dd, J = 12.2, 5.4 Hz, 1H), 4.62 (d, J = 11.5 Hz, 1H), 4.50 (d, J =11.6 Hz, 1H), 3.77 (s, 2H), 3.62 (s, 9H), 3.48-3.42 (m, 6H), 3.12-3.03(m, 2H), 2.85-2.77 (m, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.51-2.36 (m, 1H),1.93 (s, 3H), 1.87 (td, J = 15.3, 14.4, 6.5 Hz, 2H), 1.64 (t, J = 7.0Hz, 5H), 1.58- 1.46 (m, 2H), 1.25 (d, J = 6.5 Hz, 3H). H10

(4S,5R)-4-amino-5- [(4-[3-[(6-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]pro- poxy]hexyl)oxy]pro-pyl]phenyl)meth- oxy]hexanamide hydrochloride 692.4 (400 MHz, DMSO-d₆) δ7.37 (s, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.24-7.13 (m, 2H), 7.05-6.98 (m,2H), 6.90-6.81 (m, 2H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 4.51 (d, J =11.7 Hz, 1H), 4.47 (s, 1H), 4.43 (d, J = 11.7 Hz, 1H), 3.60 (dd, J =6.6, 3.6 Hz, 1H), 3.51 (d, J = 4.9 Hz, 1H), 3.42-3.30 (m, 14H), 3.09-3.02 (m, 1H), 2.95 (s, 6H), 2.93-2.84 (m, 1H), 2.79 (s, 6H), 2.05-1.96(m, 1H), 1.85- 1.73 (m, 5H), 1.71 (dd, J = 10.1, 4.8 Hz, 1H), 1.64-1.50(m, 2H), 1.54-1.46 (m, 4H). H11

(4S,5R)-4-amino-5- [(4-[3-[(6-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4-yl]pro- poxy]hexyl)oxy]pro-pyl]phenyl)meth- oxy]hexanamide hydrochloride 694.6 (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.00 (s, 2H), 7.44 (s, 1H), 7.29 (d, J = 7.7 Hz, 2H),7.18 (s, 1H), 7.16 (s, 1H), 7.00-6.83 (m, 4H), 5.38 (dd, J = 12.5, 5.3Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.25 (s,2H), 3.80-3.73 (m, 1H), 3.43 (d, J = 5.9 Hz, 1H), 3.42-3.30 (m, 9H),3.26 (s, 1H), 2.90 (s, 1H), 2.77-2.56 (m, 4H), 2.29-2.17 (m, 3H),2.04-1.95 (m, 1H), 1.82 (s, 2H), 1.83-1.69 (m, 4H), 1.51 (d, J = 7.8 Hz,5H), 1.36 (s, 4H), 1.15 (d, J = 6.3 Hz, 3H). H12

(4S,5R)-4-amino-5- [(4-[3-[(6-[3-[3- methyl-1-(1- methyl-2,6-dioxopiperidin-3- yl)-2-oxo-1,3- benzodiazol-5-yl]pro-poxy]hexyl)oxy]pro- pyl]phenyl)meth- oxy]hexanamide hydrochloride 708.6(400 MHz, DMSO-d₆) δ 7.99 (s, 2H), 7.44 (s, 1H), 7.29 (d, J = 7.8 Hz,2H), 7.17 (d, J = 7.9 Hz, 2H), 7.06-6.98 (m, 2H), 6.94- 6.82 (m, 2H),5.41 (dd, J = 12.9, 5.3 Hz, 1H), 4.78 (s, 3H), 4.57-4.42 (m, 2H), 3.82-3.73 (m, 1H), 3.42-3.31 (m, 4H), 3.27 (s, 1H), 3.04 (s, 3H), 3.02-2.92(m, 1H), 2.80 (s, 1H), 2.78-2.67 (m, 1H), 2.63 (dt, J = 20.4, 7.8 Hz,4H), 2.29-2.17 (m, 2H), 2.01 (d, J = 12.7 Hz, 1H), 1.82-1.76 (m, J =16.3, 8.0, 7.3 Hz, 6H), 1.51 (s, 5H), 1.37 (s, 4H), 1.33 (s, 4H),1.22-1.12 (m, 3H). H13

(4S,5R)-4-amino-5- [(4-[3-[(7-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]pro- poxy]heptyl)oxy]pro-pyl]phenyl)meth- oxy]hexanamide hydrochloride 708.6 (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.95 (s, 2H), 7.43 (s, 1H), 7.29 (d, J = 7.8 Hz, 2H),7.17 (d, J = 7.7 Hz, 2H), 7.05-6.97 (m, 2H), 6.93 (s, 1H), 6.86 (d, J =8.6 Hz, 1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H),4.45 (d, J = 11.7 Hz, 1H), 3.42-3.30 (m, 8H), 3.34 (s, 8H), 2.91 (s,1H), 2.73-2.56 (m, 6H), 2.28-2.17 (m, 2H), 2.01 (d, J = 8.2 Hz, 1H),1.81-1.74 (m, 4H), 1.50 (s, 5H), 1.36-1.31 (m, 5H), 1.15 (d, J = 6.5 Hz,3H). H14

(4S,5R)-4-amino-5- [(4-[3-[(8-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]pro- poxy]octyl)oxy]pro-pyl]phenyl)meth- oxy]hexanamide hydrochloride 722.7 (400 MHz, DMSO-d₆) δ7.88 (s, 1H), 7.76- 7.61 (m, 5H), 7.26 (q, J = 9.7, 8.8 Hz, 1H),7.23-7.10 (m, 1H), 7.05-6.98 (m, 1H), 6.86 (d, J = 10.2 Hz, 1H), 4.53(d, J = 11.5 Hz, 1H), 4.23 (t, J = 6.5 Hz, 5H), 3.93 (d, J = 5.8 Hz,1H), 3.65 (s, 1H), 3.57 (s, 1H), 3.33 (s, 3H), 2.67-2.58 (m, 2H), 2.19(s, 1H), 1.79 (dd, J = 17.1, 9.3 Hz, 2H), 1.71-1.59 (m, 3H), 1.45-1.31(m, 5H), 1.36 (s, 6H), 1.34-1.24 (m, 1H), 1.29 (s, 4H), 1.25 (s, 2H),1.21-1.06 (m, 2H), 0.96-0.81 (m, 9H). H15

(4S,5R)-4-amino-5- [(4-[3-[2-(2-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]pro- poxy]ethoxy)eth- oxy]pro-pyl]phenyl)meth- oxy]hexanamide hydrochloride 682.4 (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.68-7.53 (m, 4H), 7.28 (d, J = 7.6 Hz, 2H), 7.17 (d, J =7.8 Hz, 2H), 7.07-6.98 (m, 2H), 6.87 (d, J = 8.1 Hz, 1H), 5.38-5.29 (m,1H), 4.65 (d, J = 6.5 Hz, 1H), 4.57-4.42 (m, 4H), 4.21 (d, J = 8.3 Hz,2H), 4.14-4.07 (m, 3H), 3.94-3.82 (m, 3H), 3.82-3.72 (m, 3H), 3.14-3.04(m, 2H), 2.63 (dt, J = 21.6, 7.8 Hz, 6H), 2.24 (t, J = 7.6 Hz, 2H), 2.00(d, J = 15.7 Hz, 2H), 1.91 (d, J = 2.6 Hz, 2H), 1.86-1.64 (m, 7H), 1.51(d, J = 6.6 Hz, 1H). H16

(4S,5R)-4-amino-5- [(4-[3-[2-(2-[3-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]pro- poxy]ethoxy)eth-oxy]pro- pyl]phenyl)meth- oxy]hexanamide hydrochloride 682.5 (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 7.67-7.53 (m, 1H), 7.43 (s, 1H), 7.28 (d, J =7.9 Hz, 2H), 7.17 (d, J = 7.5 Hz, 2H), 6.99-6.91 (m, 3H), 6.91-6.84 (m,1H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H), 4.52 (d, J = 11.7 Hz, 1H), 4.45(d, J = 11.5 Hz, 1H), 4.16- 4.08 (m, 1H), 3.78-3.72 (m, 1H), 3.65 (s,2H), 3.56 (s, 3H), 3.40 (s, 8H), 3.27 (s, 1H), 3.00-2.83 (m, 3H),2.67-2.56 (m, 3H), 2.24 (t, J = 7.5 Hz, 2H), 2.08-1.95 (m, 2H), 1.92 (s,1H), 1.78 (ddd, J = 22.8, 15.2, 8.0 Hz, 4H), 1.77 (s, 2H), 1.19 (d, J =2.6 Hz, 1H), 1.12 (dd, J = 18.1, 6.6 Hz, 3H). H17

(4S,5R)-4-amino-5- [(4-[16-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro- 1H-1,3- benzodiazol-5-yl]- 4,7,10,13-tetraoxahexadecan-1- yl]phenyl)meth- oxy]hexanamide hydrochloride 726.6(400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.02 (s, 2H), 7.64 (t, J = 6.1 Hz,1H), 7.63-7.52 (m, 1H), 7.46 (s, 1H), 7.32-7.21 (m, 2H), 7.17 (d, J =7.9 Hz, 2H), 7.07-6.98 (m, 2H), 6.94 (s, 1H), 6.91-6.84 (m, 1H), 5.35(dd, J = 12.7, 5.3 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7Hz, 1H), 4.09-3.98 (m, 1H), 3.76 (dt, J = 8.8, 4.3 Hz, 1H), 3.66 (s,1H), 3.56-3.45 (m, 3H), 3.40 (s, 5H), 3.44-3.34 (m, 3H), 3.32 (s, 3H),3.27 (s, 1H), 2.93-2.85 (m, 1H), 2.66 (tt, J = 22.6, 8.3 Hz, 6H), 2.25(t, J = 7.5 Hz, 2H), 2.01 (d, J = 9.2 Hz, 2H), 1.80 (dd, J = 18.8, 7.8Hz, 5H), 1.77-1.67 (m, 1H), 1.27-1.04 (m, 4H). H18

(2S,4R)-1-[(2S)-2- [2-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]methyl) phenyl] acetamido]- 3,3-dimeth- ylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide hydrochloride 707.5 (400 MHz, DMSO-d₆) δ 8.60(s, 1H), 8.10 (d, J = 9.3 Hz, 1H), 8.06 (s, 2H), 7.47-7.37 (m, 4H), 7.31(d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.80 (s,1H), 4.58-4.39 (m, 4H), 4.35 (s, 1H), 4.23 (dd, J = 15.9, 5.3 Hz, 1H),3.79-3.73 (m, 1H), 3.66 (dt, J = 14.6, 5.8 Hz, 3H), 3.49-3.37 (m, 1H),3.26 (s, 1H), 2.46 (s, 3H), 2.24 (t, J = 7.2 Hz, 2H), 2.10-2.00 (m, 1H),1.96- 1.85 (m, 1H), 1.81-1.71 (m, 1H), 1.75 (s, 2H), 1.15 (d, J = 6.3Hz, 3H), 0.92 (s, 9H). H19

(2S,4R)-1-[(2S)-2- [[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]form- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 693.5 (400 MHz, CD₃OD) δ9.86 (s, 1H), 7.85 (t, J = 7.5 Hz, 2H), 7.56 (dt, J = 14.6, 8.0 Hz, 6H),4.76 (d, J = 12.3 Hz, 1H), 4.68-4.53 (m, 5H), 4.44 (d, J = 15.6 Hz, 1H),4.01 (d, J = 10.9 Hz, 1H), 3.87 (s, 2H), 3.77 (s, 1H), 3.62 (s, 1H),3.44 (s, 2H), 3.37 (s, 3H), 2.51-2.38 (m, 1H), 2.27 (s, 1H), 2.12 (s,1H), 1.99-1.83 (m, 1H), 1.31-1.28 (m, 2H), 1.12 (d, J = 11.3 Hz, 9H).H20

(2S,4R)-1-[(2S)-2- [3-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pro- panamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 721.5 (400 MHz, DMSO-d₆) δ9.01 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.07-7.98 (m, 2H), 7.94 (d, J =9.4 Hz, 1H), 7.49-7.35 (m, 4H), 7.28 (d, J = 8.1 Hz, 2H), 7.20 (d, J =7.8 Hz, 2H), 6.92 (s, 1H), 4.58-4.49 (m, 3H), 4.48- 1.43 (m, 5H), 3.76(dd, J = 6.5, 3.5 Hz, 1H), 3.66 (dd, J = 6.8, 3.0 Hz, 1H), 3.26 (d, J =7.7 Hz, 1H), 2.88-2.72 (m, 2H), 2.48- 2.41 (m, 4H), 2.24 (t, J = 7.5 Hz,2H), 2.05- 2.02 (m, 1H), 1.92 (td, J = 8.4, 4.2 Hz, 1H), 1.74 (p, J =7.5, 7.0 Hz, 2H), 1.14 (d, J = 6.4 Hz, 3H), 0.91 (s, 9H). H21

(2S,4R)-1-[(2S)-2- (2-[3-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pro- poxy]acetamido)- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 765.5 (400 MHz, DMSO-d₆) δ9.28 (s, 1H), 8.64 (d, J = 23.9 Hz, 1H), 8.18 (s, 2H), 7.43-7.38 (m,6H), 7.25 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.1 Hz, 3H), 4.54 (d, J =9.7 Hz, 1H), 4.45 (s, 2H), 4.35 (s, 1H), 4.26 (s, 1H), 3.93 (d, J = 11.7Hz, 2H), 3.77 (s, 2H), 3.46 (s, 3H), 3.39 (s, 1H), 3.16 (d, J = 12.4 Hz,2H), 2.62 (d, J = 9.4 Hz, 3H), 2.43 (s, 3H), 2.24 (s, 2H), 2.06 (s, 1H),1.82-1.76 (m, 5H), 1.12 (d, J = 6.5 Hz, 3H), 0.94 (s, 9H). H22

(2S,4R)-1-[(2S)-2- (2-[4-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]bu- toxy]acet- amido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 779.5 (400 MHz, DMSO-d₆) δ9.04 (d, J = 24.2 Hz, 1H), 8.61 (t, J = 6.2 Hz, 1H), 8.02 (d, J = 45.4Hz, 3H), 7.45-7.36 (m, 5H), 7.27 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.7Hz, 2H), 6.92 (s, 1H), 3.91 (d, J = 3.1 Hz, 2H), 3.75 (dd, J = 6.0, 3.2Hz, 1H), 3.65 (d, J = 3.2 Hz, 2H), 3.62 (s, 1H), 3.50 (s, 3H), 3.39 (d,J = 2.7 Hz, 6H), 3.17 (d, J = 3.3 Hz, 1H), 2.60 (t, J = 7.3 Hz, 2H),2.44 (s, 3H), 2.24 (t, J = 7.4 Hz, 2H), 2.07 (t, J = 10.4 Hz, 1H), 1.91(td, J = 8.8, 8.3, 4.4 Hz, 1H), 1.75 (q, J = 7.9 Hz, 2H), 1.68-1.60 (m,2H), 1.57 (d, J = 6.9 Hz, 2H), 1.14 (d, J = 6.4 Hz, 3H), 0.94 (d, J =2.9 Hz, 9H). H23

(2S,4S)-1-[(2S)-2- (2-[4-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]bu- toxy]acet- amido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 779.5 (400 MHz, CD₃OD) δ9.67 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.30(d, J = 7.5 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 4.63 (d, J = 9.1 Hz, 1H),4.58- 4.39 (m, 3H), 3.96 (d, J = 4.7 Hz, 2H), 3.88-3.84 (m, 9H),3.52-3.48 (m, 2H), 3.37 (s, 4H), 2.67 (d, J = 7.6 Hz, 2H), 2.58 (s, 3H),2.44 (dd, J = 12.7, 6.6 Hz, 1H), 1.72 (d, J = 28.6 Hz, 3H), 1.25 (d, J =6.4 Hz, 3H), 1.05 (s, 9H). H24

(2S,4R)-1-((S)-2- (5-(4-((((2R,3S)- 3,6-diamino-6- oxohexan-2-yl)oxy)meth- yl)phenyl)pentan- amido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyr- rolidine-2-carboxamide 749.4 (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.8 Hz, 1H), 8.68(s, 1H), 8.57 (t, J = 6.2 Hz, 1H), 8.06 (s, 4H), 7.85 (d, J = 9.3 Hz,1H), 7.49 (d, J = 8.2 Hz, 1H), 7.46-7.36 (m, 5H), 7.29 (d, J = 7.7 Hz,3H), 7.16 (d, J = 7.8 Hz, 4H), 6.90 (s, 1H), 4.58-4.49 (m, 2H), 4.46 (d,J = 6.5 Hz, 1H), 4.42 (dd, J = 10.8, 3.1 Hz, 1H), 4.36 (s, 1H),4.31-4.12 (m, 1H), 3.77 (td, J = 6.6, 3.8 Hz, 1H), 3.25 (s, 1H), 3.17(s, 1H), 2.56 (d, J = 7.2 Hz, 1H), 2.46 (d, J = 4.4 Hz, 4H), 2.25 (t, J= 7.4 Hz, 3H), 2.21-2.11 (m, 1H), 2.03 (d, J = 8.6 Hz, 1H), 1.93 (dd, J= 12.8, 8.4 Hz, 1H), 1.81- 1.68 (m, 2H), 1.56-1.50 (m, 4H), 1.18-1.12(m, 4H), 1.09 (d, J = 6.3 Hz, 1H), 0.93 (s, 2H). H25

(2S,4S)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]pentan- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 749.4 (400 MHz, DMSO-d₆) δ9.13-9.02 (m, 2H), 8.64 (t, J = 6.1 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H),7.51-7.31 (m, 7H), 7.28 (t, J = 6.6 Hz, 3H), 7.23-7.12 (m, 3H), 6.90 (s,1H), 4.56-4.45 (m, 3H), 4.44 (d, J = 4.4 Hz, 1H), 4.45-4.32 (m, 2H),4.31-4.12 (m, 2H), 3.93 (dd, J = 10.0, 5.7 Hz, 1H), 3.81-3.72 (m, 1H),3.47-3.36 (m, 1H), 3.40 (s, 5H), 3.26 (s, 2H), 3.17 (s, 3H), 2.56 (d, J= 7.3 Hz, 4H), 2.33-2.21 (m, 3H), 2.20-2.11 (m, 1H), 1.09 (d, J = 6.1Hz, 1H), 0.94 (s, 9H). H26

(2S,4R)-1-[(2S)-2- [2-(2-[3-[4- ([[(2R,3S)-3- amino-5- carbamoylpentan-2- yl]oxy]meth- yl)phenyl]pro- poxy]ethoxy)acet- amido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 809.5 (400MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.62 (t, J = 6.1 Hz, 1H), 8.06 (s, 2H),7.41 (d, J = 8.6 Hz, 4H), 7.27 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.8 Hz,2H), 6.92 (s, 1H), 4.60- 4.32 (m, 6H), 4.31-4.20 (m, 1H), 3.77 (d, J =8.8 Hz, 1H), 3.54 (s, 8H), 3.43 (t, J = 4.4 Hz, 2H), 3.25 (s, 1H), 2.60(t, J = 7.8 Hz, 2H), 2.44 (s, 3H), 2.25 (t, J = 7.5 Hz, 2H), 2.07 (t, J= 10.6 Hz, 1H), 1.76 (tq, J = 14.9, 6.9 Hz, 4H), 1.14 (d, J = 6.4 Hz,3H), 0.95 (s, 9H). H27

(2S,4R)-1-[(2S)-2- [2-[2-(2-[3-[4- ([[(2R,3S)-3- amino-5-carbamoylpentan- 2- yl]oxy]meth- yl)phenyl]pro- poxy]ethoxy)eth-oxy]acetamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride853.6 (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.06(s, 3H), 7.41 (s, 5H), 7.28 (d, J = 7.3 Hz, 2H), 7.17 (t, J = 9.3 Hz,2H), 6.92 (s, 1H), 4.60-4.50 (m, 2H), 4.48-4.41 (m, 2H), 4.41-4.33 (m,2H), 4.25 (dd, J = 15.9, 5.7 Hz, 1H), 4.14 (d, J = 5.7 Hz, 1H), 3.98 (s,1H), 3.81-3.73 (m, 1H), 3.65 (d, J = 3.8 Hz, 2H), 3.61 (s, 2H),3.52-3.47 (m, 5H), 3.39-3.24 (m, 4H), 3.25 (s, 1H), 2.64-2.54 (m, 2H),2.45 (s, 3H), 2.25 (t, J = 7.5 Hz, 3H), 1.80-1.72 (m, 5H), 1.15 (dd, J =6.3, 2.0 Hz, 3H), 0.95 (s, 9H). H28

(2S,4R)-1-[(2S)-2- [15-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]- 3,6,9,12- tetraoxapentadecan- amido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 897.6 (400MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.61 (t, J = 6.0 Hz, 1H), 7.98 (s, 3H),7.42 (d, J = 12.3 Hz, 6H), 7.29 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 8.0Hz, 2H), 6.93 (s, 1H), 4.61- 4.49 (m, 2H), 4.49-4.34 (m, 4H), 4.25 (dd,J = 15.8, 5.7 Hz, 1H), 3.97 (s, 2H), 3.76 (s, 1H), 3.71-3.64 (m, 1H),3.62 (s, 3H), 3.57-3.43 (m, 4H), 3.40-3.35 (m, 4H), 3.27 (s, 1H), 2.59(t, J = 7.6 Hz, 2H), 2.45 (s, 3H), 2.24 (t, J = 7.5 Hz, 2H), 2.12-2.02(m, 1H), 1.96-1.86 (m, 2H), 1.75 (h, J = 7.8, 7.3 Hz, 4H), 1.18-1.10 (m,4H), 0.95 (s, 9H). H29

(2S,4R)-1-[(2S)-2- [4-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]butan- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 735.4 Used directly in nextstep without further purification H30

(2S,4R)-1-[(2S)-2- (2-[2-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]eth- oxy]acet- amido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 751.5 (400 MHz, DMSO-d₆) δ9.02 (s, 1H), 8.63 (t, J = 6.1 Hz, 1H), 7.99 (s, 3H), 7.46-7.36 (m, 4H),7.33-7.19 (m, 4H), 6.93 (s, 1H), 4.59-4.51 (m, 1H), 4.51-4.35 (m, 3H),4.36 (s, 1H), 4.27 (dd, J = 15.8, 5.7 Hz, 1H), 3.95 (s, 2H), 3.78-3.67(m, 1H), 3.39 (s, 3H), 3.26 (s, 1H), 3.17 (s, 1H), 2.95 (s, 1H), 2.87(t, J = 6.8 Hz, 2H), 2.79 (s, 1H), 2.44 (s, 3H), 2.24 (t, J = 7.5 Hz,2H), 2.07 (t, J = 10.3 Hz, 1H), 1.99-1.85 (m, 2H), 1.79-1.70 (m, 1H),1.15-1.12 (m, 3H), 0.93 (s, 9H). H31

(2S,4R)-1-[(2S)-2- [2-(2-[2-[4- ([[(2R,3S)-3- amino-5- carbamoylpentan-2- yl]oxy]meth- yl)phenyl]eth- oxy]ethoxy)acet- amido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 795.6 (400MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.61 (t, J = 5.9 Hz, 1H), 8.01 (s, 3H),7.30-7.17 (m, 3H), 6.91 (s, 1H), 4.62-4.41 (m, 5H), 4.40 (d, J = 8.9 Hz,1H), 4.37 (s, 2H), 4.26 (dd, J = 15.9, 5.7 Hz, 2H), 3.97 (s, 3H), 3.76(d, J = 6.0 Hz, 2H), 3.49 (d, J = 6.5 Hz, 1H), 3.40 (s, 6H), 3.27 (s,1H), 3.18 (s, 1H), 2.85-2.82 (m, 3H), 2.43 (s, 2H), 2.25 (t, J = 7.5 Hz,2H), 2.12-1.99 (m, 2H), 1.97-1.86 (m, 1H), 1.74 (dd, J = 14.8, 7.4 Hz,2H), 1.15 (d, J = 6.4 Hz, 4H), 1.08 (d, J = 6.2 Hz, 1H), 0.96 (s, 9H).H32

(2S,4R)-1-[(2S)-2- [2-[2-(2-[2-[4- ([[(2R,3S)-3- amino-5-carbamoylpentan- 2- yl]oxy]meth- yl)phenyl]eth- oxy]ethoxy)eth-oxy]acetamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride839.6 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.61 (t, J = 6.1 Hz, 1H), 7.94(s, 3H), 7.43 (d, J = 9.1 Hz, 3H), 7.40 (s, 3H), 7.28 (d, J = 7.9 Hz,2H), 7.20 (d, J = 7.9 Hz, 2H), 6.93 (s, 1H), 4.61-4.49 (m, 2H),4.48-4.35 (m, 4H), 3.97 (s, 2H), 3.57 (t, J = 10.4 Hz, 10H), 3.39 (s,2H), 3.27 (s, 1H), 2.77 (t, J = 6.9 Hz, 2H), 2.44 (s, 3H), 2.26-2.21 (m,5H), 1.74 (p, J = 7.5 Hz, 2H), 1.18-1.12 (m, 3H), 0.95 (s, 9H). H33

(2S,4R)-1-[(2S)-2- [14-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]- 3,6,9,12- tetraoxatetradecan- amido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 883.7 (400MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.65- 8.48 (m, 1H), 8.11 (s, 3H), 7.41 (s,5H), 7.29 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.91 (s, 1H),4.60-4.49 (m, 2H), 4.49-4.40 (m, 2H), 4.40-4.34 (m, 2H), 4.25 (dd, J =15.8, 5.7 Hz, 1H), 3.81-3.73 (m, 2H), 3.66 (d, J = 3.8 Hz, 1H),3.64-3.59 (m, 3H), 3.56-3.53 (m, 3H), 3.53-3.50 (m, 3H), 3.48 (s, 4H),3.40 (s, 2H), 3.25 (s, 1H), 2.78 (t, J = 7.0 Hz, 2H), 2.46 (s, 3H), 2.25(t, J = 7.9 Hz, 2H), 2.07 (t, J = 10.4 Hz, 1H), 1.91 (ddd, J = 13.0,8.7, 4.6 Hz, 1H), 1.80- 1.71 (m, 2H), 1.17-1.12 (m, 3H), 0.95 (s, 9H).H34

(2S,4R)-1-((S)-2- (6-(4-((((2R,3S)- 3,6-diamino-6- oxohexan-2-yl)oxy)meth- yl)phenyl)hexan- amido)- 3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl) pyrrolidine-2-carboxamide 763.4 (400 MHz, DMSO-d₆) δ 9.08 (d, J = 1.1 Hz, 1H), 8.58(t, J = 6.1 Hz, 1H), 8.10 (s, 3H), 7.84 (d, J = 9.3 Hz, 1H), 7.51-7.37(m, 5H), 7.33-7.25 (m, 2H), 7.19-7.14 (m, 2H), 6.91 (s, 1H), 4.58-4.49(m, 2H), 4.45-4.40 (m, 3H), 4.35 (s, 1H), 4.22 (dd, J = 15.9, 5.4 Hz,1H), 3.82-3.74 (m, 1H), 3.67-3.63 (m, 1H), 3.61 (s, 1H), 3.39 (s, 1H),3.25 (s, 1H), 2.58-2.53 (m, 2H), 2.46 (d, J = 4.2 Hz, 3H), 2.30-2.21 (m,3H), 2.17-2.00 (m, 2H), 1.90 (ddd, J = 12.9, 8.6, 4.6 Hz, 1H), 1.81-1.72 (m, 2H), 1.59-1.46 (m, 4H), 1.27 (q, J = 7.6 Hz, 2H), 1.15 (d, J =6.4 Hz, 3H), 0.93 (d, J = 3.6 Hz, 9H). H35

(2S,4R)-1-[(2S)-2- [7-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]heptan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 777.7 (400 MHz, CD₃OD) δ9.90 (d, J = 15.5 Hz, 1H), 7.65-7.48 (m, 4H), 7.33-7.29 (m, 2H), 7.19(d, J = 7.8 Hz, 2H), 4.64-4.46 (m, 10H), 2.62 (s, 4H), 2.48-2.41 (m,4H), 2.33-2.26 (m, 3H), 2.10 (s, 2H), 1.94 (s, 2H), 1.63 (s, 4H), 1.38(s, 4H), 1.26 (d, J = 6.4 Hz, 3H), 1.06 (s, 9H). H36

(4S,5R)-4-amino-5- [[4-(3-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-4- yl]methoxy]pro- pyl)phenyl]meth- oxy]hexanamidehydrochloride 566.4 (400 MHz, CD₃OD) δ 7.27 (d, J = 7.8 Hz, 2H),7.18-7.08 (m, 3H), 7.08 (q, J = 3.7 Hz, 2H), 5.38 (dd, J = 12.3, 5.4 Hz,1H), 4.98 (s, 2H), 4.76 (s, 2H), 4.62 (d, J = 11.6 Hz, 1H), 4.49 (d, J =11.6 Hz, 1H), 3.80 (qd, J = 6.4, 3.4 Hz, 1H), 3.70 (s, 3H), 3.53 (t, J =6.2 Hz, 2H), 3.02-2.85 (m, 1H), 2.88- 2.76 (m, 2H), 2.67 (t, J = 7.5 Hz,2H), 2.52- 2.33 (m, 2H), 2.24-2.14 (m, 1H), 2.01-1.78 (m, 2H), 1.59 (s,1H), 1.25 (d, J = 6.4 Hz, 3H). H37

(4S,5R)-4-amino-5- [[4-(5-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-5- yl]propoxy] pentyl)phenyl] methoxy] hexanamidehydrochloride 622.4 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.92 (s, 3H),7.42 (s, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.01(d, J = 10.0 Hz, 2H), 6.93 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.34 (dd,J = 12.7, 5.2 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 4.45 (d, J = 11.6 Hz,1H), 4.14-4.10 (m, 3H), 3.87 (s, 2H), 3.75 (d, J = 3.5 Hz, 1H), 3.61(dd, J = 7.4, 3.4 Hz, 1H), 3.52-3.50 (m, 1H), 3.38-3.32 (m, 4H),2.68-2.62 (m, 3H), 2.58 (t, J = 7.6 Hz, 2H), 2.24 (s, 1H), 2.02-1.97 (m,1H), 1.81 (d, J = 8.6 Hz, 2H), 1.75 (d, J = 9.1 Hz, 1H), 1.54 (dt, J =13.6, 7.7 Hz, 4H), 1.35-1.31 (m, 3H), 1.14 (d, J = 6.4 Hz, 3H). H38

(4S,5R)-4-amino-5- [[4-(5-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-4- yl]propoxy]pen- tyl)phenyl]meth- oxy]hexanamidehydrochloride 622.5 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.44 (s, 1H),7.28 (d, J = 7.7 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 5.9 Hz,2H), 6.93 (d, J = 7.0 Hz, 1H), 6.86 (dd, J = 6.5, 2.4 Hz, 1H), 5.38 (dd,J = 12.5, 5.4 Hz, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.44 (d, J = 11.7 Hz,1H), 3.75 (dd, J = 6.5, 3.5 Hz, 1H), 3.65 (s, 1H), 3.61 (dd, J = 7.7,4.0 Hz, 1H), 3.54 (s, 3H), 3.51 (d, J = 5.3 Hz, 2H), 3.42 (d, J = 5.9Hz, 2H), 3.36 (d, J = 6.4 Hz, 2H), 3.26 (s, 1H), 2.92 (s, 2H), 2.74-2.62 (m, 2H), 2.60-2.53 (m, 3H), 2.23 (d, J = 7.5 Hz, 1H), 1.80-1.72 (m,4H), 1.60- 1.52 (m, 4H), 1.38-1.31 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H).H39

(4S,5R)-4-amino-5- [[4-(2-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-4- yl]propoxy]eth- yl)phenyl]meth- oxy]hexanamidehydrochloride 580.3 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.98 (s, 2H),7.43 (s, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H),6.99-6.90 (m, 2H), 6.81 (d, J = 7.2 Hz, 1H), 5.37 (dd, J = 12.6, 5.3 Hz,1H), 4.63 (s, 3H), 4.54 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H),3.76 (dd, J = 6.5, 3.4 Hz, 1H), 3.68-3.56 (m, 2H), 3.55-3.37 (m, 5H),3.27 (s, 1H), 2.95-2.89 (m, 3H), 2.83 (t, J = 6.7 Hz, 2H), 2.74-2.63 (m,1H), 2.24 (t, J = 7.4 Hz, 2H), 1.99 (d, J = 12.3 Hz, 1H), 1.83-1.74 (m,3H), 1.73 (d, J = 7.7 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H). H40

(4S,5R)-4-amino-5- [(4-[4-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-4- yl]bu- tyl]phenyl)meth- oxy]hexanamidehydrochloride 550.5 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.26-8.04 (m,3H), 7.29 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 6.95 (h, J =7.8, 5.8 Hz, 3H), 6.85 (dd, J = 6.9, 1.9 Hz, 1H), 5.38 (dd, J = 12.6,5.4 Hz, 1H), 4.57-4.42 (m, 2H), 3.78 (qd, J = 6.3, 3.1 Hz, 1H), 3.51 (s,3H), 3.25 (s, 1H), 2.98-2.86 (m, 3H), 2.71 (dd, J = 15.0, 10.6 Hz, 1H),2.63 (q, J = 7.8, 7.2 Hz, 3H), 2.26 (t, J = 7.5 Hz, 2H), 1.99 (dd, J =11.4, 5.6 Hz, 1H), 1.84- 1.57 (m, 6H), 1.15 (d, J = 6.2 Hz, 3H). H41

(4S,5R)-4-amino-5- [(4-[5-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-4- yl]pen- tyl]phenyl)meth- oxy]hexanamidehydrochloride 564.5 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.99 (s, 2H),7.44 (s, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H),6.99-6.91 (m, 2H), 6.85 (dd, J = 6.6, 2.4 Hz, 1H), 5.37 (dd, J = 12.6,5.3 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 3.76(dd, J = 6.5, 3.5 Hz, 1H), 3.48 (s, 1H), 3.40 (s, 1H), 3.27 (s, 1H),2.92-2.86 (m, 3H), 2.72 (dd, J = 15.2, 10.8 Hz, 1H), 2.66-2.55 (m, 3H),2.24 (t, J = 7.4 Hz, 2H), 2.03-1.96 (m, 1H), 1.74 (dq, J = 14.7, 7.1 Hz,2H), 1.63 (s, 5H), 1.41 (s, 2H), 1.15 (d, J = 6.3 Hz, 3H). H42

(4S,5R)-4-amino-5- ([4-[3-([5-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-5- yl]pentyl]oxy)pro- pyl]phenyl]meth-oxy)hexanamide hydrochloride 622.4 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.86 (s, 3H), 7.41 (s, 1H), 7.32-7.21 (m, 3H), 7.17 (d, J = 7.9 Hz, 2H),7.05-6.96 (m, 2H), 6.94 (s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 4.54 (d, J =11.4 Hz, 1H), 4.45 (d, J = 11.8 Hz, 1H), 3.51 (d, J = 3.3 Hz, 1H),3.36-3.31 (m, 4H), 2.63-2.58 (m, 7H), 2.27-2.19 (m, 2H), 1.76 (s, 6H),1.61 (s, 3H), 1.58-1.50 (m, 2H), 1.35 (s, 3H), 1.24 (s, 1H), 1.15 (d, J= 6.4 Hz, 3H). H43

(4S,5R)-4-amino-5- ([4-[3-([5-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-4- yl]pentyl]oxy)pro- pyl]phenyl]meth-oxy)hexanamide hydrochloride 622.4 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.96 (s, 2H), 7.43 (s, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8Hz, 2H), 6.99-6.91 (m, 3H), 6.91-6.84 (m, 1H), 5.37 (dd, J = 12.5, 5.4Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 3.76 (d,J = 7.5 Hz, 1H), 3.65 (s, 1H), 3.58 (s, 5H), 3.42-3.31 (m, 5H), 3.27 (s,1H), 2.93-2.87 (m, 3H), 2.67-2.56 (m, 3H), 2.24 (t, J = 7.4 Hz, 2H),1.99 (d, J = 11.9 Hz, 1H), 1.77 (s, 3H), 1.65-1.53 (m, 2H), 1.45 (d, J =7.4 Hz, 2H), 1.24-1.11 (m, 3H), 0.11 (s, 1H). H44

(2S,4R)-N-[[2-([5- [4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pen- tyl]oxy)-4- (4-methyl-1,3- thiazol-5-yl)phenyl]methyl]- 1-[(2S)-2-[(1- fluorocyclo- propyl)formamido]- 3,3-dimethylbutanoyl]- 4- hydroxypyrrolidine- 2-carboxamide hydrochloride837.6 (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.52 (t, J = 5.9 Hz, 1H), 8.01(s, 3H), 7.48-7.37 (m, 2H), 7.29 (d, J = 7.9 Hz, 3H), 7.19 (d, J = 7.9Hz, 2H), 7.00 (s, 1H), 6.98-6.87 (m, 2H), 4.60 (d, J = 9.2 Hz, 1H),4.57-4.50 (m, 2H), 4.45 (d, J = 11.6 Hz, 1H), 4.37 (s, 1H), 4.30-4.25(m, 1H), 4.24-4.17 (m, 1H), 4.05 (t, J = 6.2 Hz, 2H), 3.77 (dd, J = 6.8,3.4 Hz, 1H), 3.62 (s, 2H), 3.48 (s, 1H), 3.26 (s, 1H), 2.61 (t, J = 7.7Hz, 2H), 2.46 (s, 3H), 2.24 (t, J = 7.5 Hz, 2H), 2.11 (t, J = 10.3 Hz,1H), 1.93 (t, J = 6.4 Hz, 1H), 1.81-1.78 (m, 3H), 1.64 (q, J = 7.8 Hz,2H), 1.49 (d, J = 7.5 Hz, 2H), 1.37 (dd, J = 18.4, 9.6 Hz, 2H), 1.23 (d,J = 8.0 Hz, 2H), 1.15 (d, J = 6.3 Hz, 3H), 0.97 (s, 9H). H45

(2S,4R)-N-[(2-[4- [4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]butoxy]- 4-(4- methyl-1,3-thiazol-5-yl)phenyl)methyl]- 1-[(2S)-2-[(1- fluorocyclo- propyl)formamido]- 3,3-dimethylbutanoyl]-4- hydroxypyrrolidine- 2-carboxamide hydrochloride823.6 (400 MHz, CD₃OD) δ 10.06-9.88 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H),7.32 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.4 Hz,2H), 4.69-4.61 (m, 2H), 4.56- 4.48 (m, 3H), 4.14 (s, 2H), 3.92-3.75 (m,3H), 3.68-3.66 (m, 4H), 3.62 (s, 2H), 3.38 (d, J = 9.9 Hz, 1H), 2.74 (s,2H), 2.62 (d, J = 1.4 Hz, 3H), 2.44 (h, J = 8.5 Hz, 1H), 2.25 (t, J =10.5 Hz, 1H), 2.18-2.07 (m, 1H), 1.89 (s, 6H), 1.42-1.29 (m, 1H), 1.26(d, J = 6.4 Hz, 3H), 1.06 (s, 9H). H46

(2S,4R)-N-[(2-[2- [2-(2-[3-[4- ([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]pro- poxylethoxy)eth- oxy]ethoxy]-4-(4-methyl-1,3- thiazol-5- yl)phenyl)methyl]- 1-[(2S)-2-[(1- fluorocyclo-propyl)formamido]- 3,3- dimethylbutanoyl]- 4- hydroxypyrrolidine-2-carboxamide hydrochloride [(M/ 2 + 1)]⁺ = 471.6 (400 MHz, DMSO-d₆) δ9.02 (s, 1H), 8.50 (t, J = 5.9 Hz, 1H), 8.01 (s, 3H), 7.41 (d, J = 7.8Hz, 1H), 7.25-7.12 (m, 6H), 7.04 (d, J = 1.7 Hz, 1H), 6.97 (d, J = 7.9Hz, 1H), 6.91 (s, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.57- 4.48 (m, 2H),4.45 (d, J = 11.7 Hz, 1H), 4.38-4.26 (m, 3H), 4.23 (d, J = 5.7 Hz, 1H),4.19 (s, 2H), 3.80-2.77 (m, 4H), 3.70-3.60 (m, 2H), 3.54-3.51 (m, 2H),3.49-3.43 (m, 2H), 3.37 (t, J = 6.5 Hz, 2H), 3.26 (s, 1H), 2.59 (t, J =7.7 Hz, 2H), 2.46 (s, 3H), 2.24 (t, J = 7.5 Hz, 2H), 2.10 (t, J = 10.3Hz, 1H), 1.99-1.86 (m, 1H), 1.76-1.70 (m, 5H), 1.43-1.31 (m, 2H),1.26-1.19 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H), 0.96 (s, 10H). H47

(2S,4R)-N-[[2-([15- [4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]-3,6,9,12- tetraoxapentadecan- 1-yl]oxy)-4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl]- 1-[(2S)-2-[(1- fluorocyclo-propyl)formamido]- 3,3- dimethylbutanoyl]- 4- hydroxypyrrolidine-2-carboxamide hydrochloride [(M/ 2 + 1)]⁺ = 493.6 (400 MHz, DMSO-d₆) δ9.01 (s, 1H), 8.48 (d, J = 6.1 Hz, 1H), 7.97 (s, 3H), 7.41 (d, J = 8.0Hz, 1H), 7.30-7.27 (m, 3H), 7.17 (d, J = 7.9 Hz, 2H), 7.04 (s, 1H), 6.97(d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.56-4.49(m, 2H), 4.45 (d, J = 11.7 Hz, 1H), 4.36 (s, 2H), 4.31 (d, J = 10.3 Hz,1H), 4.31-4.21 (m, 1H), 4.19 (d, J = 5.0 Hz, 2H), 3.80-3.74 (m, 3H),3.68-3.60 (m, 3H), 3.58-3.49 (m, 7H), 3.49-3.44 (m, 2H), 3.40-3.36 (m,4H), 3.27 (s, 1H), 2.59 (t, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.24 (t, J =7.4 Hz, 2H), 2.10 (t, J = 9.3 Hz, 1H), 1.98-1.87 (m, 1H), 1.77-1.72 (m,4H), 1.37 (dd, J = 18.5, 9.2 Hz, 2H), 1.23 (d, J = 9.3 Hz, 2H), 1.15 (d,J = 6.3 Hz, 3H), 0.96 (s, 9H). H48

(2S,4R)-N-[[2-([18- [4-[[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]- 3,6,9,12,15- pentaoxaoctadecan- 1-yl]oxy)-4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl]- 1-[(2S)-2-[(1- fluorocyclo-propyl)formamido]- 3,3- dimethylbutanoyl]- 4-hydroxy- pyrrolidine-2-carboxamide hydrochloride [(M/ 2 + 1)]⁺ = 515.7 (400 MHz, DMSO-d₆) δ9.02 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.02 (s, 3H), 7.63 (dd, J =11.9, 7.1 Hz, 1H), 7.45-7.34 (m, 1H), 7.31-7.29 (m, 3H), 7.17 (d, J =7.8 Hz, 2H), 7.04 (s, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.91 (s, 1H), 4.60(d, J = 9.2 Hz, 1H), 4.56-4.49 (m, 2H), 4.45 (d, J = 11.5 Hz, 1H), 4.38-4.26 (m, 2H), 4.26-4.08 (m, 3H), 3.83-3.73 (m, 3H), 3.70-3.59 (m, 3H),3.56-3.44 (m, 14H), 3.40-3.36 (m, 5H), 3.26 (s, 1H), 2.60 (t, J = 7.7Hz, 2H), 2.47 (s, 3H), 2.25 (t, J = 7.5 Hz, 2H), 2.10 (t, J = 10.4 Hz,1H), 1.99-1.88 (m, 1H), 1.80-1.73 (m, 4H), 1.43-1.30 (m, 2H), 1.26-1.19(m, 2H), 1.15 (d, J = 6.3 Hz, 3H), 0.96 (s, 9H). H49

(2S,4R)-N-[(2-[3- [4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]propoxy]- 4-(4-methyl-1,3- thiazol-5-yl)phenyl)methyl]- 1-[(2S)-2-[(1- fluorocyclo- propyl)formamido]- 3,3-dimethylbutanoyl]- 4- hydroxypyrrolidine- 2-carboxamide hydrochloride809.6 (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 7.97 (s, 3H), 7.42 (d, J = 8.1Hz, 2H), 7.33-7.30 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 7.3Hz, 2H), 6.93 (s, 1H), 4.61 (d, J = 9.1 Hz, 1H), 4.57-4.50 (m, 2H), 4.46(d, J = 11.7 Hz, 1H), 4.38-4.21 (m, 3H), 4.05 (s, 3H), 3.75 (s, 1H),3.39 (s, 2H), 3.27 (s, 1H), 2.79 (t, J = 7.6 Hz, 2H), 2.45 (s, 3H), 2.24(t, J = 7.5 Hz, 2H), 2.12-2.03 (m, 3H), 1.74 (d, J = 16.2 Hz, 1H), 1.74(s, 1H), 1.38 (dd, J = 18.5, 9.7 Hz, 1H), 1.25-1.21 (m, 3H), 1.15 (d, J= 6.4 Hz, 3H), 0.97 (s, 9H). H50

(2S,4R)-N-[[2-(2- [3-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]pro- poxy]ethoxy)- 4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl]- 1-[(2S)-2-[(1- fluorocyclo- propyl)formamido]- 3,3-dimethylbutanoyl]- 4- hydroxypyrrolidine- 2-carboxamide hydrochloride853.5 (400 MHz, CDCl₃) δ 8.71 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.32(d, J = 5.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H),7.07 (dd, J = 9.0, 3.4 Hz, 1H), 6.99 (dd, J = 7.7, 1.5 Hz, 1H), 6.94 (d,J = 1.6 Hz, 1H), 6.39 (s, 1H), 5.51 (s, 1H), 4.95 (d, J = 9.7 Hz, 1H),4.67 (t, J = 7.8 Hz, 1H), 4.61-4.54 (m, 2H), 4.51 (q, J = 6.2, 5.6 Hz,2H), 4.47-4.35 (m, 3H), 4.22 (q, J = 5.2 Hz, 2H), 3.95 (d, J = 11.0 Hz,1H), 3.90- 3.82 (m, 3H), 3.66 (dd, J = 11.1, 3.9 Hz, 2H), 3.60-3.56 (m,3H), 2.71 (t, J = 7.5 Hz, 2H), 2.55 (s, 3H), 2.42 (dt, J = 13.0, 6.9 Hz,1H), 2.27 (d, J = 9.5 Hz, 2H), 1.99-1.91 (m, 4H), 1.76-1.66 (m, 1H),1.35-1.26 (m, 4H), 1.22 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H). H51

(2S,4R)-N-([2-[2- (2-[3-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pro- poxy]ethoxy)eth- oxy]-4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl)- 1-[(2S)-2-[(1- fluorocyclo-propyl)formamido]- 3,3- dimethylbutanoyl]- 4- hydroxypyrrolidine-2-carboxamide hydrochloride 897.7 (400 MHz, CD₃OD) δ 9.39 (s, 1H), 7.55(d, J = 7.8 Hz, 1H), 7.31-7.28 (m, 3H), 7.23- 7.19 (m, 3H), 7.12 (s,1H), 7.08 (d, J = 8.2 Hz, 2H), 4.62 (s, 5H), 4.53-4.48 (m, 5H), 4.44 (s,2H), 4.29 (s, 4H), 3.96 (d, J = 4.7 Hz, 4H), 2.71-2.68 (m, 4H), 2.56 (s,5H), 2.48-2.43 (m, 4H), 2.22 (s, 2H), 2.08 (s, 2H), 1.93 (d, J = 5.2 Hz,3H), 1.89-1.84 (m, 5H), 1.39-1.30 (m, 8H), 1.30-1.22 (m, 4H). H52

(4S,5R)-4-amino-5- [(4-[4-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-5- yl]butyl]phenyl) methoxy]hexanamidehydrochloride 550.2 crude to next step without further purification H53

(4S,5R)-4-amino-5- [(4-[6-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-5- yl]hexyl]phenyl) methoxy] hexanamidehydrochloride 578.5 crude to next step without further purification H54

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5-(methyl-carbamoyl)pentan- 2-yl]oxy]meth- yl)phenyl]pentan- amido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 763.6 (400MHz, DMSO-d₆) δ 9.11 (d, J = 2.1 Hz, 1H), 8.60 (t, J = 6.1 Hz, 1H), 8.12(s, 3H), 7.98 (s, 1H), 7.88 (d, J = 9.4 Hz, 1H), 7.46-7.37 (m, 4H), 7.28(d, J = 7.8 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 4.54 (d, J = 8.7 Hz, 2H),4.51-4.38 (m, 3H), 4.35 (s, 1H), 4.22 (dd, J = 15.7, 5.2 Hz, 1H),3.85-3.75 (m, 1H), 3.71-3.59 (m, 2H), 3.23 (s, 1H), 2.60-2.52 (m, 5H),2.46 (s, 3H), 2.26 (t, J = 7.5 Hz, 2H), 2.20-2.11 (m, 1H), 2.04 (t, J =10.1 Hz, 1H), 1.90 (ddd, J = 12.9, 8.3, 4.6 Hz, 1H), 1.75 (h, J = 6.9Hz, 2H), 1.55- 1.40 (m, 5H), 1.14 (d, J = 6.4 Hz, 3H), 0.93 (s, 9H). H55

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pentan- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth-yl]pyrrolidine-2- carboxamide hydrochloride 763.3 (400 MHz, CD₃OD) δ10.10-9.93 (m, 1H), 7.62-7.51 (m, 4H), 7.31 (d, J = 7.9 Hz, 2H), 7.20(d, J = 8.0 Hz, 2H), 5.04 (q, J = 7.0 Hz, 1H), 4.68-4.49 (m, 4H), 4.45(s, 1H), 3.90 (d, J = 11.1 Hz, 1H), 3.87-3.79 (m, 1H), 3.76 (dd, J =11.0, 3.9 Hz, 1H), 3.65- 3.58 (m, 1H), 3.37 (q, J = 6.1, 5.2 Hz, 1H),2.67 (d, J = 6.9 Hz, 2H), 2.63 (s, 3H), 2.53- 2.17 (m, 3H), 2.01-1.79(m, 2H), 1.73-1.61 (m, 5H), 1.53 (d, J = 7.0 Hz, 3H), 1.28-1.23 (m, 3H),1.22-1.17 (m, 1H), 1.06 (s, 8H), 1.03 (s, 1H). H56

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pentan- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[1-[4- (4-methyl-1,3- thiazol-5- yl)phenyl]cyclo-propyl]pyrrolidine- 2-carboxamide hydrochloride 775.4 Used directly innext step without further purification H57

(2S,4R)-1-[(2S)-2- [6-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]hex-5- ynamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide; trifluoro- acetaldehyde 759.3 Useddirectly in next step without further purification H58

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pent-4- ynamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide; trifluoro- acetaldehyde 745.3 Useddirectly in next step without further purification H59

(4S,5R)-4-amino-5- [3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3- benzodiazol-5- yl]propoxy]hexan- amide hydrochloride 446.2 Useddirectly in next step without further purification H60

(2S,4R)-1-[(2S)-2- [5-[3-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pentan- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 749.3 (400 MHz, CD₃OD) δ9.96 (s, 1H), 7.57 (m, 4H), 7.32-7.18 (m, 3H), 7.15 (d, J = 7.4 Hz, 1H),4.70-4.47 (m, 6H), 4.43 (d, J = 15.8 Hz, 1H), 3.93 (d, J = 10.9 Hz, 1H),3.83 (ddd, J = 10.5, 7.3, 4.2 Hz, 2H), 3.39 (dd, J = 8.3, 4.0 Hz, 1H),2.66 (dd, J = 14.7, 7.6 Hz, 2H), 2.62 (s, 3H), 2.53-2.36 (m, 2H),2.35-2.16 (m, 2H), 2.15-2.02 (m, 1H), 2.02-1.80 (m, 2H), 1.70-1.60 (m,5H), 1.33-1.16 (m, 3H), 1.05 (s, 9H). H61

(2S,4R)-1-[(2S)-2- [6-[2-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]hexan- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 763.6 Used directly in nextstep without further purification H62

(2S,4R)-1-[(2S)-2- [3-[6-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)naphthalen-2- yl]propanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 771.3 Used directly in nextstep without further purification H63

tert-butyl N- [(3S,4R)-1- carbamoyl-4-[[7- (2-[[(2S)-1- [(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]meth-yl]carbamoyl)pyr- rolidin-1-yl]-3,3- dimethyl-1- oxobutan-2-yl]carbamoyl]eth- yl)naphthalen-2- yl]methoxy]pentan- 3-yl]carbamate.771.40 Used in the next step without further purification H64

(2S,4R)-1-[(2S)-2- [4-[6-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)naphthalen-2- yl]butanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide 785.40 (400 MHz, CD₃OD) δ 7.85-7.75 (m,4H), 7.68 (s, 1H), 7.58-7.47 (m, 5H), 7.40 (dd, J = 8.5, 1.7 Hz, 1H),4.81 (s, 1H), 4.75-4.65 (m, 2H), 4.65-4.52 (m, 2H), 4.53 (s, 1H), 4.41(d, J = 15.7 Hz, 1H), 3.95 (d, J = 11.0 Hz, 1H), 3.92-3.79 (m, 2H),3.45-3.39 (m, 1H), 2.83 (q, J = 8.7, 7.8 Hz, 2H), 2.57 (s, 3H), 2.53-2.30 (m, 3H), 2.29-2.20 (m, 1H), 2.15-2.02 (m, 2H), 2.01 (s, 2H), 2.00-1.81 (m, 2H), 1.29 (d, J = 6.4 Hz, 3H), 1.07 (s, 9H) H65

(2S,4R)-1-((S)-2- (3-(6-((((2R,3S)- 3,6-diamino-6- oxohexan-2-yl)oxy)meth- yl)naphthalen-1- yl)propanamido)- 3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyr- rolidine-2-carboxamide hydrochloride 771.30 (400 MHz, DMSO-d₆) δ 9.09 (s, 1H),8.61 (t, J = 6.0 Hz, 1H), 8.15 (s, 3H), 8.08-8.06 (m, 2H), 7.92 (d, J =1.7 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 8.8, 1.7 Hz, 1H),7.52-7.34 (m, 6H), 6.93 (s, 1H), 5.76 (s, 1H), 4.75 (d, J = 12.2 Hz,1H), 4.68 (d, J = 12.1 Hz, 1H), 4.59 (d, J = 9.4 Hz, 1H), 4.49-4.35 (m,2H), 4.25-4.18 (m, 1H), 4.07-4.05 (m, 1H), 3.86 (dd, J = 6.5, 3.4 Hz,1H), 3.69 (d, J = 4.3 Hz, 2H), 3.39 (s, 1H), 3.33-3.20 (m, 3H),2.77-2.65 (m, 1H), 2.59-2.56 (m, 1H), 2.45 (s, 3H), 2.27 (t, J = 7.5 Hz,2H), 2.05 (d, J = 8.3 Hz, 1H), 2.01-1.87 (m, 1H), 1.79-1.77 (m, 2H),1.26-1.23 (m, 3H), 0.93 (s, 9H). H66

(2S,4R)-1-((S)-2- (4-(6-((((2R,3S)- 3,6-diamino-6- oxohexan-2-yl)oxy)meth- yl)naphthalen-1- yl)butanamido)- 3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyr- rolidine-2-carboxamide 785.35 (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.7 Hz, 1H), 8.58(t, J = 6.1 Hz, 1H), 8.19-8.03 (m, 4H), 7.97 (d, J = 9.3 Hz, 1H), 7.90(s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.51-7.36(m, 5H), 7.33 (d, J = 6.9 Hz, 1H), 6.92 (s, 1H), 4.80-4.63 (m, 2H), 4.60(d, J = 9.4 Hz, 1H), 4.51-4.38 (m, 2H), 4.37-4.33 (m, 4H), 3.85 (d, J =6.6 Hz, 1H), 3.69-3.65 (m, 2H), 3.40-3.36 (m, 2H), 3.33-3.30 (m, 1H),3.05-3.01 (m, 2H), 2.45 (s, 3H), 2.30-2.25 (m, 3H), 2.05- 2.03 (m, 1H),1.97-1.74 (m, 3H), 1.20 (d, J = 6.4 Hz, 3H), 0.95 (s, 9H). H67

(2S,4R)-1-[(2S)-2- [(5E)-6-[4- ([[(2R,3S)-3- amino-5- carbamoylpentan-2- yl]oxy]meth- yl)phenyl]hex- 5-enamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide 761.30 Used in the next step withoutfurther purification H68

(2S,4R)-1-[(2S)-2- [(4E)-5-[4- ([[(2R,3S)-3- amino-5- carbamoylpentan-2- yl]oxy]meth- yl)phenyl]pent-4- enamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide 747.30 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H),8.61- 8.55 (m, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.87-7.84 (m, 1H),7.46-7.37 (m, 4H), 7.36-7.30 (m, 6H), 7.20 (s, 3H), 7.07 (s, 3H), 6.93(s, 1H), 6.42 (d, J = 15.9 Hz, 1H), 4.61-4.39 (m, 4H), 4.36 (s, 1H),4.22 (dd, J = 15.9, 5.4 Hz, 1H), 3.73-3.60 (m, 2H), 2.45 (s, 3H), 2.34(d, J = 2.2 Hz, 1H), 2.24 (t, J = 7.4 Hz, 1H), 2.04 (s, 1H), 1.91 (d, J= 3.6 Hz, 1H), 1.78-1.70 (m, 1H), 1.24 (s, 3H), 1.14 (d, J = 6.4 Hz,2H), 1.11-1.01 (m, 1H), 0.93 (s, 9H) H69

1-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2- yl]oxy]meth-yl)phenyl]-N- [(2S)-1- [(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]carbamoyl)pyr-rolidin-1-yl]-3,3- dimethyl-1- oxobutan-2- yl]piperidine-4- carboxamidehydrochloride 776.30 Used in the next step without further purificationH70

(2S,4R)-1-[(2S)-2- (2-[1-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan-2-2-yl]oxy]meth- yl)phenyl]piperidin- 4- yl]acetamido)-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 790.65 (400MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.24-8.02 (m,3H), 7.93-7.87 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.41 (q, J = 8.4 Hz,4H), 4.61-4.49 (m, 2H), 4.48-4.40 (m, 1H), 4.37 (s, 16H), 4.23 (dd, J =16.0, 5.1 Hz, 1H), 3.86-3.79 (m, 1H), 3.73-3.62 (m, 2H), 3.44-3.34 (m,1H), 3.27 (s, 1H), 2.46 (s, 3H), 2.26-2.03 (m, 3H), 2.05 (t, J = 10.3Hz, 1H), 1.96-1.85 (m, 1H), 1.79-1.73 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H),1.10 (t, J = 7.0 Hz, 1H), 0.96 (s, 9H) H71

(2S,4R)-1-((S)-2- (3-(1-(4-((((2R,3S)- 3,6-diamino-6- oxohexan-2-yl)oxy)meth- yl)phenyl)piperidin-4- yl)propanamido)- dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyr- rolidine-2-carboxamide [(M − 1)]⁻ = 802.55 (400 MHz, DMSO-d₆) δ 9.04 (s, 1H),8.60 (t, J = 6.1 Hz, 1H), 8.18-8.12 (m, 2H), 7.98 (d, J = 9.3 Hz, 1H),7.86 (s, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.41 (q, J = 8.3 Hz, 5H), 6.92(s, 1H), 4.65-4.50 (m, 3H), 4.48-4.41 (m, 2H), 4.22 (dd, J = 16.0, 5.4Hz, 1H), 3.88-3.79 (m, 1H), 3.68 (s, 2H), 3.53-3.48 (m, 4), 3.39 (q, J =7.0 Hz, 2H), 3.27 (s, 1H), 2.45 (s, 3H), 2.26 (t, J = 7.5 Hz, 3H),2.09-2.03 (m, 1H), 1.96-1.87 (m, 3), 1.83- 1.71 (m, 1H), 1.67-1.54 (m,4H), 1.18 (d, J = 6.4 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H), 0.96 (s, 9H)H72

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[7-[3-(2,6- dioxopiperidin-3-yl)-1-methyl-2- oxo-1,3- benzodiazol-5- yl]heptanoyl]-6- oxo-octahydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]- (diphenylmeth-yl)pentanediamide trifluoroacetate 890.35 ¹H NMR (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.86 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 5.3 Hz, 2H),7.39-7.22 (m, 12H), 7.12-7.05 (m, 1H), 7.02-6.97 (m, 1H), 6.91 (d, J =8.1 Hz, 1H), 6.79 (s, 1H), 6.11 (d, J = 8.4 Hz, 1H), 5.36 (dd, J = 12.8,5.4 Hz, 1H), 4.52- 4.45 (m, 2H), 4.42-4.35 (m, 1H), 4.26-4.14 (m, 2H),3.98-3.89 (m, 1H), 3.85-3.78 (m, 1H), 3.32 (m, 3H), 3.24-3.12 (m, 1H),2.97-2.89 (m, 1H), 2.81-2.70 (m, 1H), 2.68-2.55 (m, 3H), 2.36-2.08 (m,4H), 2.06-1.98 (m, 5H), 1.81-1.75 (m, 1H), 1.70 (d, J = 9.8 Hz, 2H),1.62-1.54 (m, 5H), 1.37-1.32 (m, 4H) H73

(2S,4R)-1-[(2S)-2- [5-(4-[[(2S)-4- Carbamoyl-2- (chloro-amino)butoxy]meth- yl]phenyl)pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth-yl]pyrrolidine-2- carboxamide hydrochloride 749.30 (400 MHz, DMSO-d₆) δ9.22 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.30-8.10 (m, 3H), 7.83 (d, J =9.1 Hz, 1H), 7.55-7.36 (m, 4H), 7.28 (d, J = 7.6 Hz, 2H), 7.17 (d, J =7.6 Hz, 2H), 6.91 (s, 1H), 4.91 (q, J = 7.1 Hz, 1H), 4.56-4.37 (m, 4H),4.27 (s, 1H), 3.63-3.58 (m, 6H), 2.62-2.53 (m, 2H), 2.48 (s, 3H),2.35-1.97 (m, 3H), 1.82-1.76 (m, 2H), 1.59 (s, 7H), 1.37 (d, J = 6.9 Hz,3H), 0.93 (s, 9H) H74

(2S,4R)-1-[(2S)-2- [4-[4- (aminometh- yl)phenyl]butan- amido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 606.30 (400MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.28 (br, 2H),7.92 (d, J = 9.3 Hz, 1H), 7.46-7.34 (m, 6H), 7.23 (d, J = 8.0 Hz, 2H),4.56 (d, J = 9.4 Hz, 1H), 4.48-4.39 (m, 2H), 4.36 (s, 1H), 4.22 (dd, J =15.9, 5.4 Hz, 1H), 4.02-3.97 (m, 2H), 3.69-3.65 (m, 2H), 2.59-2.55 (m,2H), 2.45 (s, 3H), 2.36-2.24 (m, 1H), 2.18-2.15 (m, 1H), 2.06-2.02 (m,1H), 1.92-1.89 (m, 1H), 1.79-1.76 (m, 2H), 0.95 (s, 9H) H75

(2S)-2-amino-N- [[4-(3-[[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl]car- bamoyl)pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]pro- pyl)phenyl]meth-yl]pentanediamide hydrochloride 734.30 (400 MHz, DMSO-d₆) δ 9.04 (s,1H), 8.98 (t, J = 5.7 Hz, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.33-8.29 (m,3H), 7.92 (d, J = 9.3 Hz, 1H), 7.46-7.37 (m, 5H), 7.22 (d, J = 8.1 Hz,2H), 7.16 (d, J = 8.1 Hz, 2H), 6.95 (s, 1H), 4.59- 4.54 (m, 1H), 4.43(t, J = 8.0 Hz, 2H), 4.36 (d, J = 4.7 Hz, 1H), 4.31 (dd, J = 9.8, 5.5Hz, 2H), 4.26-4.22 (m, 2H), 2.45 (s, 3H), 2.31-2.24 (m, 1H), 2.20-2.12(m, 4H), 2.09-2.01 (m, 2H), 2.00-1.87 (m, 4H), 1.86-1.75 (m, 3H), 0.95(s, 9H) H76

(2S,4R)-1-[(2S)-2- [5-[4- (aminometh- yl)phenyl]pentan- amido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide 620.20 (400 MHz, DMSO-d₆)δ 9.05 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.32 (s, 2H), 7.88 (d, J = 9.3Hz, 1H), 7.40 (dd, J = 8.9, 7.2 Hz, 6H), 7.23 (d, J = 8.1 Hz, 2H), 3.57(m, 7H), 2.95 (s, 4H), 2.79 (m, 2H), 2.37-2.25 (m, 1H), 2.21-2.13 (m,1H), 2.04 (m, J = 10.5 Hz, 1H), 1.96 (m, 2H), 1.60 (m, 1H), 1.58- 1.38(m, 4H), 1.24 (m, 1H), 0.94 (s, 9H) H77

(2S)-2-amino-N- [[4-(4-[[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl]car- bamoyl)pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2-yl]car- bamoyl]bu- tyl)phenyl]meth-yl]pentanediamide hydrochloride 748.25 Used in the next step withoutfurther purification H78

(2S,4R)-1-[(2S)-2- [6-[4- (aminometh- yl)phenyl]hexan- amido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 634.30 (400MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.39 (s, 1H),7.86 (d, J = 9.3 Hz, 1H), 7.48-7.36 (m, 5H), 7.26- 7.18 (m, 2H), 5.07(s, 1H), 4.59-4.52 (m, 1H), 4.48-4.40 (m, 2H), 4.38-4.34 (m, 1H), 4.22(dd, J = 15.8, 5.2 Hz, 1H), 4.03- 3.84 (m, 2H), 3.75-3.60 (m, 2H), 2.56(t, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.26 (dt, J = 14.8, 7.5 Hz, 1H),2.18-1.98 (m, 2H), 1.92- 1.87 (m, 1H), 1.59-1.42 (m, 4H), 1.29-1.25 (m,2H), 0.94 (s, 9H). H79

(2S)-2-amino-N- [[4-(5-[[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]meth- yl]carbamoyl)pyr-rolidin-1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]pen-tyl)phenyl]meth- yl]pentanediamide hydrochloride 762.35 (400 MHz,DMSO-d₆) δ 9.03 (s, 1H), 8.96 (m, J = 5.7 Hz, 1H), 8.59 (d, J = 6.0 Hz,1H), 8.32-8.27 (m, 2H), 7.86-7.85 (m, 1H), 7.43-7.39 (m, 5H), 7.22-7.14(m, 4H), 6.97-6.95 (m, 1H), 4.59-4.50 (m, 1H), 4.46-4.42 (m, 2H),4.37-4.19 (m, 5H), 4.03-3.84 (m, 2H), 3.75-3.60 (m, 2H), 2.45 (s, 3H),2.30-2.17 (m, 3H), 2.17-2.01 (m, 2H), 1.99-1.89 (m, 3H), 1.61-1.52 (m,6H), 1.28-1.24 (m, 2H), 0.93 (s, 9H) H80

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[3-(2-[2- [1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]ethyl]phenyl)pro-panoyl]-6-oxo- octa- hydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]-N-(diphenylmeth- yl)pentanediamide trifluoroacetates 938.30 (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.87-8.76 (m, 1H), 8.30-8.26 (m, 3H),7.37-7.09 (m, 14H), 7.02 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H),6.80 (d, J = 21.5 Hz, 1H), 6.15-6.04 (m, 1H), 5.34 (d, J = 13.0 Hz, 1H),4.50-4.24 (m, 4H), 4.24- 3.85 (m, 3H), 3.80 (t, J = 19.8 Hz, 2H),3.42-3.40 (m, 1H), 3.34 (s, 3H), 3.27-3.07 (m, 1H), 2.95-2.85 (m, 6H),2.79-2.57 (m, 5H), 2.29-1.38 (m, 11H) H81

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[3- [(1r,4r)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]methyl]cyclohex- yl]propanoyl]- octa- hydropyrrolo[1,2-a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)pentanediamidetrifluoroacetate 930.35 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.73 (d, J =8.4 Hz, 1H), 8.18-8.16 (m, 2H), 7.39-7.18 (m, 11H), 7.02-6.96 (m, 2H),6.81 (dd, J = 8.1, 1.7 Hz, 1H), 6.72 (d, J = 19.1 Hz, 1H), 6.47 (d, J =6.9 Hz, 1H), 6.09 (d, J = 8.3 Hz, 1H), 5.76 (s, 2H), 5.34 (dd, J = 12.6,5.4 Hz, 1H), 4.43-4.27 (m, 2H), 4.09-4.01 (m, 1H), 3.70-3.66 (m, 2H),3.32-3.30 (m, 11H), 3.24-3.04 (m, 1H), 2.98-2.84 (m, 1H), 2.75-2.60 (m,2H), 2.47-2.44 (m, 1H), 2.17-2.04 (m, 3H), 2.09-1.90 (m, 2H), 1.83-1.56(m, 6H), 1.43-1.34 (m, 2H), 1.18 (t, J = 7.1 Hz, 1H), 0.98-0.79 (m, 4H)H82

(2S,4R)-1-[(2S)-2- [2-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]methyl)- [1,1-biphenyl]-3- yl]acetamido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 783.30 (400MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.20-8.15 (m,4H), 7.64-7.60 (m, 3H), 7.54-7.46 (m, 4H), 7.46-7.37 (m, 4H), 7.37-7.19(m, 2H), 6.93 (s, 1H), 4.64-4.51 (m, 3H), 4.49-4.39 (m, 2H), 4.35 (s,1H), 4.23 (dd, J = 15.8, 5.5 Hz, 1H), 3.84 (dd, J = 6.5, 3.3 Hz, 1H),3.75 (d, J = 13.7 Hz, 1H), 3.71-3.59 (m, 2H), 3.28 (s, 1H), 2.46 (s,3H), 2.28 (t, J = 7.5 Hz, 2H), 2.05 (t, J = 10.3 Hz, 1H), 1.94- 1.87 (m,1H), 1.84-1.72 (m, 2H), 1.24 (s, 1H), 1.19 (d, J = 6.4 Hz, 3H), 0.93 (s,9H) H83

(2S,4R)-1-[(2S)- 3,3-dimethyl-2- [[(1r,3r)-3-[[4- ([[(2R,3S)-3- amino-5-carbamoylpentan- 2- yl]oxy]meth- yl)phenyl]meth- yl]cyclo-butyl]formamido]bu- tanoyl]-4-hydroxy- N- [[4-(4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 761.35 (400MHz, DMSO-d₆) δ 9.04 (d, J = 2.0 Hz, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.03(s, 4H), 7.69 (d, J = 9.3 Hz, 1H), 7.46-7.34 (m, 4H), 7.28 (dd, J = 7.8,4.4 Hz, 2H), 7.14 (t, J = 7.8 Hz, 2H), 6.92 (s, 1H), 4.59-4.49 (m, 2H),4.43 (dd, J = 14.9, 9.4 Hz, 4H), 4.22 (dd, J = 15.8, 5.4 Hz, 1H), 3.77(d, J = 7.6 Hz, 1H), 3.66 (s, 1H), 3.26 (s, 2H), 3.05 (p, J = 8.7 Hz,1H), 2.62 (d, J = 7.5 Hz, 2H), 2.46 (d, J = 4.7 Hz, 1H), 2.45 (s, 3H),2.24 (t, J = 7.5 Hz, 2H), 2.07 (dd, J = 36.2, 8.7 Hz, 3H), 1.96-1.84 (m,2H), 1.75 (tt, J = 15.1, 8.4 Hz, 3H), 1.60 (s, 3H), 1.16 (t, J = 6.2 Hz,3H), 0.92 (s, 9H); H84

(2S,4R)-1-[(2S)-2- [2-(3-[[4- ([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]meth- yl]cyclo- butyl)acetamido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 775.35 ¹HNMR (400 MHz, CD₃OD) δ 10.07 (s, 1H), 7.58 (q, J = 8.0 Hz, 4H),7.37-7.26 (m, 2H), 7.16 (t, J = 7.9 Hz, 2H), 4.66-4.62 (m, 1H),4.64-4.48 (m, 7H), 4.45-4.41 (m, 1H), 3.94-3.77 (m, 3H), 3.66-3.47 (m,1H), 3.41-3.37 (m, 1H), 2.77 (d, J = 7.8 Hz, 1H), 2.71-2.65 (m, 2H),2.64 (s, 3H), 2.63-2.54 (m, 1H), 2.54-2.29 (m, 4H), 2.30-2.15 (m, 1H),2.14-2.02 (m, 1H), 2.03-1.91 (m, 1H), 1.91-1.80 (m, 1H), 1.52-1.47 (m,1H), 1.26 (s, 3H), 1.24-1.16(m, 1H), 1.04 (d, J = 2.7 Hz, 9H) H85

(2S,4R)-1-[(2S)-2- (2-[3-[4-([[(2R,3S)- 3-amino-5-car- bamoylpentan-2-yl]oxy]meth- yl)phenyl]cyclo- butyl]acetamido)- 3,3-dimethyl- butanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 761.35 (400 MHz, CD₃OD) δ10.01-9.95 (m, 1H), 7.63-7.51 (m, 4H), 7.37-7.20 (m, 4H), 4.69-4.65 (m,1H), 4.66-4.49 (m, 6H), 4.43 (d, J = 15.7 Hz, 1H), 3.93 (d, J = 11.0 Hz,1H), 3.88-3.79 (m, 2H), 3.66-3.54 (m, 1H), 3.43-3.34 (m, 2H), 2.82-2.63(m, 1H), 2.63 (d, J = 1.0 Hz, 3H), 2.61-2.50 (m, 1H), 2.51-2.29 (m, 3H),2.30-2.20 (m, 2H), 2.15-2.02 (m, 1H), 2.02-1.79 (m, 2H), 1.62-1.58 (m,1H), 1.25 (s, 3H), 1.06 (s, 9H) H86

(2S)-2- ((5S,8S,10aR)-5- amino-3-(2-(4-((1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro- 1H- benzo[d]imidazol- 5-yl)methyl)piperazin- 1-yl)acetyl)-6- oxodecahydro- pyrrolo[1,2-a][1,5]diazocine-8- carboxamido)-N1- benzhydrylpentane diamidetrifluoroacetate 918.54 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.74 (d, J =8.4 Hz, 1H), 8.21-8.17 (m, 1H), 7.38-7.20 (m, 15H), 7.10 (d, J = 1.4 Hz,1H), 7.05 (d, J = 8.0 Hz, 1H), 6.97 (dd, J = 8.1, 1.4 Hz, 1H), 6.75-6.70(m, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.36 (dd, J = 12.7, 5.5 Hz, 1H),4.42-4.29 (m, 3H), 4.10-3.95 (m, 1H), 3.81-3.69 (m, 1H), 3.47 (s, 3H),3.26- 3.05 (m, 5H), 3.00-2.86 (m, 3H), 2.77-2.58 (m, 2H), 2.49-2.22 (m,10H), 2.16-2.09 (m, 2H), 2.06-1.70 (m, 2H), 1.68-1.49 (m, 2H), 1.32-1.17(m, 2H) H87

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[2-(4-[[1- (2,6- Dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzoazol-5- yl]methyl]piperidin-1-yl)acetyl]-6-oxo- octahydro- pyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N-(diphenylmeth- yl)pentanediamide trifluoroacetate917.40 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 9.41 (s, 1H), 8.85-8.69 (m,1H), 8.48-8.26 (m, 2H), 7.40-7.18 (m, 11H), 7.04 (h, J = 4.1, 3.5 Hz,2H), 6.91-6.75 (m, 2H), 6.10 (d, J = 8.2 Hz, 1H), 5.36 (dd, J = 12.9,5.4 Hz, 1H), 4.74-4.18 (m, 4H), 3.53-3.38 (m, 1H), 3.33 (s, 3H),3.18-2.80 (m, 6H), 2.78-2.54 (m, 4H), 2.20-2.08 (m, 4H), 2.01-1.85 (m,2H), 1.88-1.64 (m, 12H), 1.63-1.49 (m, 2H) H88

(2S)-2- [[(5S,8S,10aR)-3- (4-[4-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]piperidin-1-yl]butanoyl)-6-oxo- 5-(2,2,2- trifluoroacetamido)- octahydro-pyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]- N- (diphenylmeth-yl)pentanediamide trifluoroacetate 931.40 (400 MHz, DMSO-d₆) δ 11.10 (s,1H), 9.50 (s, 1H), 8.83-8.74 (m, 1H), 8.46-8.27 (m, 2H), 7.41-7.14 (m,11H), 7.13-6.97 (m, 2H), 6.92 (dt, J = 8.2, 1.9 Hz, 1H), 6.80 (d, J =13.5 Hz, 1H), 6.11 (d, J = 8.4 Hz, 1H), 5.37 (dd, J = 12.8, 5.4 Hz, 1H),4.64-4.14 (m, 5H), 3.93-3.85 (m, 5H), 3.35 (s, 3H), 3.20-2.97 (m, 6H),2.99-2.79 (m, 3H), 2.79-2.57 (m, 4H), 2.29-1.60 (m, 10H), 1.31-1.20 (m,1H), 0.86-0.82 (m, 1H) H89

(2S)-2- [[(5S,8S,10aR)-3- (3-[4-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]piperidin-1- yl]propanoyl)-6-oxo-5-(2,2,2- trifluoro- acetamido)- octahydro- pyrrolo[1,2-a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)pentanediamidetrifluoroacetate 917.45 (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 9.43-9.26(m, 1H), 8.89-8.25 (m, 3H), 7.37-7.18 (m, 11H), 7.12-6.98 (m, 2H),6.96-6.88 (m, 1H), 6.81 (d, J = 15.4 Hz, 1H), 6.11 (d, J = 8.3 Hz, 1H),5.37 (dd, J = 12.7, 5.5 Hz, 1H), 4.68-4.30 (m, 4H), 3.69- 3.59 (m, 4H),3.48-3.37 (m, 5H), 3.35 (s, 3H), 3.15-3.06 (m, 5H), 2.97-2.77 (m, 3H),2.78-2.57 (m, 3H), 2.30-1.87 (m, 8H), 1.87-1.79 (m, 3H) H90

(2S,4R)-1-[(2S)-2- [2-(4-[[4- ([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]meth- yl]piperidin- 1-yl)acetamido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide trifluoroacetate 804.35Used in the next step without further purification H91

(2S,4R)-1-[(2S)-2- (6-[4-[(2S)-2- Amino-4- carbamoylbu-toxy]phenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3- thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamidehydrochloride 735.30 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.58 (t, J = 6.0Hz, 1H), 8.28-8.23 (m, 3H), 7.84 (d, J = 9.4 Hz, 1H), 7.41 (q, J = 8.4Hz, 5H), 7.15-7.08 (m, 2H), 6.98-6.86 (m, 2H), 4.61-4.50 (m, 1H),4.48-4.40 (m, 2H), 4.36 (s, 1H), 4.28-4.09 (m, 2H), 3.71-3.61 (m, 2H),3.53-3.47 (m, 1H), 2.56-2.54 (m, 1H), 2.51-2.47 (m, 1H), 2.46 (s, 3H),2.37-2.20 (m, 3H), 2.16-1.99 (m, 2H), 1.97-1.80 (m, 3H), 1.59-1.42 (m,4H), 1.26 (q, J = 7.5 Hz, 2H), 0.94 (s, 9H) H92

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl]hexan- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3- thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamidehydrochloride 735.34 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.57 (t, J = 6.1Hz, 1H), 8.30-8.26 (m, 2H), 7.84 (d, J = 9.3 Hz, 1H), 7.41 (q, J = 8.3Hz, 4H), 7.21 (t, J = 7.9 Hz, 1H), 6.92 (s, 1H), 6.86-6.75 (m, 3H), 4.54(d, J = 9.3 Hz, 1H), 4.47-4.39 (m, 2H), 4.36 (s, 1H), 4.18-4.11 (m, 3H),4.02 (dd, J = 10.5, 6.5 Hz, 1H), 3.71-3.60 (m, 2H), 3.50 (s, 1H),3.06-3.02 (m, 2H), 2.45 (s, 3H), 2.34-2.23 (m, 3H), 2.17-1.99 (m, 2H),1.97-1.83 (m, 3H), 1.78-1.71 (m, 2H), 1.62-1.41 (m, 5H), 1.31-1.25 (m,2H), 0.93 (s, 9H) H93

(2S,4R)-1-[(2S)-2- [3-(4-[3-[(2S)-2- amino-4- carbamoylbu-toxy]propyl]phen- yl)propanamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 771.42 Used in the next stepwithout further purification H94

(2S,4R)-1-[(2S)-2- [5-[4-([[(2S)-2- amino-4- carbamoylbu- tyl](meth-yl)amino]meth- yl)phenyl]pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 748.40 Used in the next stepwithout further purification H95

(2S)-2- [[(5S,8S,10aR)-5- amino-3-(8-[[(2S)- 1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]meth-yl]carbamoyl)pyr- rolidin-1-yl]-3,3- dimethyl-1- oxobutan-2-yl]car-bamoyl]octanoyl)- 6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N- (diphenylmeth- yl)pentanediamide hydrochloride1103.39 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.59- 8.54 (m, 1H), 8.30 (s,3H), 7.85 (d, J = 9.2 Hz, 1H), 7.46-7.29 (m, 10H), 7.31-7.24 (m, 6H),6.79 (s, 1H), 6.10 (d, J = 8.4 Hz, 1H), 4.55 (d, J = 9.1 Hz, 1H),4.48-4.40 (m, 2H), 4.20 (s, 2H), 3.60-3.55 (m, 5H), 2.71-2.63 (m, 1H),2.47-2.43 (m, 5H), 2.36- 2.32 (m, 2H), 2.13-2.08 (m, 8H), 1.54-1.50 (m,4H), 1.32-1.21 (m, 9H), 1.17-1.14 (m, 1H), 0.96-0.92 (m, 14H) H96

(2S)-2- [[(5S,8S,10aR)-5- amino-3-(10-[[(2S)- 1-[(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]car-bamoyl)pyrrolidin- 1-yl]-3,3- dimethyl-1- oxobutan-2-yl]car-bamoyl]decanoyl)- 6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N- (diphenylmeth- yl)pentanediamide hydrochloride1131.50 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.86 (t, J = 7.6 Hz, 1H),8.33 (s, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.45-7.22 (m, 16H), 6.79 (s,1H), 6.11 (d, J = 7.8 Hz, 1H), 4.55 (d, J = 9.2 Hz, 1H), 4.48-4.39 (m,5H), 4.36 (s, 2H), 3.68-3.38 (m, 11H), 2.48-2.44 (m, 7H), 2.18-1.69 (m,3H), 1.58-1.53 (m, 6H), 1.3-1.25 (m, 15H), 0.95 (s, 9H) H97

(2S,4S)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]meth- yl)phenyl]pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth-yl]pyrrolidine-2- carboxamide hydrochloride 763.45 (400 MHz, CD₃OD) δ10.07 (s, 1H), 7.62- 7.51 (m, 4H), 7.31 (d, J = 7.9 Hz, 2H), 7.20 (d, J= 7.9 Hz, 2H), 5.04 (q, J = 7.0 Hz, 1H), 4.64 (d, J = 11.6 Hz, 1H),4.56-4.45 (m, 3H), 4.39 (t, J = 4.6 Hz, 1H), 4.03 (dd, J = 10.7, 5.1 Hz,1H), 3.88-3.80 (m, 1H), 3.42-3.35 (m, 1H), 2.64 (s, 3H), 2.47-2.43 (m,2H), 2.35-2.31 (m, 1H), 1.99-1.82 (m, 2H), 1.65 (s, 6H), 1.64-1.60 (m,4H), 1.53 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.07 (s, 9H)H98

(2S)-2- [(5S,8S,10aR)-5- amino-3-[7-[3- methyl-1-(1- methyl-2,6-dioxopiperidin-3- yl)-2-oxo-1,3- benzodiazol-5- yl]heptanoyl]-6-octahydropyrrolo[l,2- a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)pentanediamide trifluoroacetate 904.40 (400 MHz,DMSO-d₆) δ 8.84 (t, J = 8.0 Hz, 1H), 8.38-8.23 (m, 3H), 7.77-7.10 (m,13H), 7.05-6.97 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 6.11(d, J = 8.4 Hz, 1H), 5.41 (dd, J = 12.9, 5.3 Hz, 1H), 4.52-4.32 (m, 3H),4.28-4.14 (m, 1H), 3.97 (d, J = 14.2 Hz, 1H), 3.82 (d, J = 14.2 Hz, 1H),3.50-3.42 (m, 1H), 3.34 (s, 3H), 3.29-3.08 (m, 1H), 3.04 (s, 3H),3.01-2.91 (m, 1H), 2.84-2.67 (m, 2H), 2.62 (t, J = 7.7 Hz, 2H),2.48-2.10 (m, 4H), 2.06-1.98 (m, 1H), 1.98- 1.85 (m, 2H), 1.85-1.65 (m,4H), 1.65- 1.44 (m, 4H), 1.43-1.19 (m, 4H). H99

(2S,4R)-1-[(2S)-2- [10-[(2S)-2-amino-4- carbamoylbu- toxy]decanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 715.40 (400MHz, DMSO-d₆) δ 9.08 (d, J = 4.9 Hz, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.05(s, 2H), 7.84 (d, J = 9.3 Hz, 1H), 7.48-7.36 (m, 5H), 6.90 (s, 1H),4.58-4.50 (m, 1H), 4.48-4.39 (m, 2H), 4.35 (s, 1H), 4.23 (dd, J = 15.8,5.2 Hz, 1H), 3.71-3.60 (m, 2H), 3.52 (dd, J = 10.4, 4.0 Hz, 1H),3.47-3.36 (m, 3H), 3.23 (s, 1H), 2.46 (s, 3H), 2.28- 2.21 (m, 3H),2.16-1.99 (m, 2H), 1.94-1.87 (m, 1H), 1.81-1.70 (m, 2H), 1.58-1.46 (m,4H), 1.28-1.23 (m, 12H), 0.94 (s, 9H) H100

(2S,4R)-1-[(2S)-2- [9-[(2S)-2-amino-4- carbamoylbu- toxy]nonan-amido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride701.25 (400 MHz, DMSO-d₆) δ 9.26-9.03 (m, 1H), 8.61-8.57 (m, 1H), 7.84(d, J = 9.3 Hz, 1H), 7.57-7.31 (m, 5H), 6.90 (s, 1H), 4.88- 4.50 (m,1H), 4.46-4.37 (m, 2H), 4.37-4.30 (m, 1H), 4.28-4.25 (m, 1H), 3.74-3.61(m, 2H), 3.52 (dd, J = 10.4, 4.0 Hz, 1H), 3.46- 3.32 (m, 4H), 3.23 (s,1H), 2.46 (s, 3H), 2.27-2.24 (m, 3H), 2.17-2.01 (m, 2H), 1.91 (td, J =8.5, 4.3 Hz, 1H), 1.78-1.75 (m, 2H), 1.52-1.47 (m, 6H), 1.28-1.22 (m8H), 0.94 (s, 9H) H101

(2S,4R)-1-((S)-2- (8-(((S)-2,5- diamino-5- oxopentyl)oxy)octan-amido)-3,3- dimethylbutanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyr- rolidine- 2-carboxamide hydrochloride 687.55 (400 MHz,DMSO-d₆) δ 9.05 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H), 8.10-7.97 (m, 2H),7.84 (d, J = 9.3 Hz, 1H), 7.48-7.37 (m, 5H), 6.90 (s, 1H), 4.58-4.16 (m,5H), 3.72-3.61 (m, 2H), 3.55-3.35 (m, 4H), 3.23 (s, 1H), 3.13- 2.99 (m,2H), 2.45 (s, 3H), 2.33-2.00 (m, 4H), 1.94-1.69 (m, 3H), 1.56-1.40 (m,2H), 1.35-1.16 (m, 9H), 0.94 (s, 9H) H102

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(5S,8S,10aR)-3-acetyl-5-amino-6- oxo- octa- hydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]-5- carbamoylpentan- 2- yl]oxy]meth- yl)phenyl]pentan-amido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride1000.45 (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.59 (s, 1H), 8.50 (s, 1H),8.37 (d, J = 17.5 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 9.3Hz, 1H), 7.41 (q, J = 8.1 Hz, 4H), 7.22 (d, J = 7.7 Hz, 2H), 7.13 (d, J= 7.7 Hz, 3H), 6.71 (s, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.44 (d, J = 13.8Hz, 5H), 4.35 (s, 1H), 4.21 (d, J = 15.7 Hz, 2H), 4.03 (d, J = 14.4 Hz,1H), 3.76 (s, 2H), 3.63 (dd, J = 16.7, 6.0 Hz, 2H), 3.45-3.37 (m, 2H),3.28-3.23 (m, 1H), 3.19-3.16 (m, 1H), 3.15-3.11 (m, 1H), 2.55 (s, 2H),2.45 (s, 3H), 2.35-2.27 (m, 1H), 2.30-1.99 (m, 6H), 1.98-1.65 (m, 2H),1.54-1.49 (m, 10H), 1.41-1.33 (m, 1H), 1.26-1.22 (m, 1H), 1.07 (d, J =6.1 Hz, 3H), 0.93 (s, 9H) H103

(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6- oxo- octa- hydropyrrolo[1,2-a][1,5]diazocin- 8-yl]formamido]- N-(7-[[(2S)-1- [(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]meth- yl]car-bamoyl)pyrrolidin- 1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]hep-ty1)pentanediamide hydrochloride 951.80 (400 MHz, DMSO-d₆) δ 9.02 (d, J= 5.0 Hz, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.28 (s, 2H), 7.92 (s, 1H),7.85 (d, J = 9.3 Hz, 1H), 7.46-7.36 (m, 4H), 7.25 (s, 1H), 6.76 (s, 1H),4.58-4.52 (m, 1H), 4.52-4.39 (m, 3H), 4.36 (s, 1H), 4.27 (s, 1H),4.31-4.17 (m, 2H), 4.10-3.96 (m, 2H), 3.95-3.80 (m, 2H), 3.72-3.60 (m,6H), 3.57 (s, 1H), 3.47-3.37 (m, 1H), 3.29-3.18 (m, 1H), 3.07-3.02 (m,1H), 2.45 (s, 3H), 2.29-2.24 (m, 2H), 2.21- 1.99 (m, 7H), 1.93-1.89 (m,1H), 1.84- 1.70 (m, 2H), 1.55-1.47 (m, 1H), 1.43-1.33 (m, 2H), 1.26-1.22(m, 8H), 0.94 (s, 9H) H104

(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6- oxo- octahydropyrrolo[1,2-a][1,5]diazocin- 8-yl]formamido]- N-(8-[[(2S)-1- [(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]car-bamoyl)pyrrolidin- 1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]oc-tyl)pentane- diamide hydrochloride 965.80 (400 MHz, DMSO-d₆) δ 9.04 (d,J = 8.6 Hz, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 8.31 (d, J = 19.3 Hz, 2H),7.93 (s, 1H), 7.89-7.82 (m, 1H), 7.46-7.36 (m, 4H), 7.26 (s, 1H), 6.77(s, 1H), 4.58-4.52 (m, 1H), 4.48-4.44 (m, 3H), 4.35 (s, 1H), 4.31-4.13(m, 3H), 3.81-3.73 (m, 1H), 3.73-3.57 (m, 3H), 3.53-3.37 (m, 1H),3.29-2.96 (m, 2H), 2.46 (s, 3H), 2.28-2.24 (m, 2H), 2.21-1.99 (m, 7H),1.92-1.89 (m, 1H), 1.83-1.80 (m, 9H), 1.80-1.65 (m, 2H), 1.60-1.42 (m,1H), 1.41-1.34 (m, 2H), 1.26-1.10 (m, 8H), 0.94 (s, 9H) H105

(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6- oxo- octahydropyrrolo[l,2-a][1,5]diazocin- 8-yl]formamido]- N-(9-[[(2S)-1- [(2S,4R)-4-hydroxy-2-([[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]car-bamoyl)pyrrolidin- 1-yl]-3,3- dimethyl-1- oxobutan-2-yl]car-bamoyl]nonyl)pentane- diamide hydrochloride 979.60 (400 MHz, DMSO-d₆) δ9.04 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.47 (s, 1H), 8.36-8.25 (m, 2H),7.92 (t, J = 5.5 Hz, 1H), 7.84 (d, J = 9.4 Hz, 1H), 7.46-7.36 (m, 4H),7.31- 7.19 (m, 1H), 6.76 (s, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.46 (s,2H), 4.52-4.39 (m, 2H), 4.36 (s, 1H), 4.27-4.17 (m, 2H), 4.01 (d, J =12.9 Hz, 1H), 3.81-3.57 (m, 5H), 3.59- 3.55 (m, 5H), 3.53-3.35 (m, 1H),3.26-3.22 (m, 1H), 3.15-2.97 (m, 2H), 2.46 (s, 3H), 2.32-2.17 (m, 2H),2.12-2.08 (m, 6H), 1.93-1.89 (m, 1H), 1.85-1.66 (m, 2H), 1.58-1.42 (m,2H), 1.39-1.35 (m, 3H), 1.26-1.06 (m, 10H), 0.94 (s, 9H) H106

(2R)-2- [[(5S,8S,10aR)-5- amino-3-[7-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]heptanoyl]-6- oxo-octahydropyrrolo[l,2- a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)pentanediamide trifluoroacetate 890.55 (400 MHz,CD₃OD) δ 7.39-7.31 (m, 6H), 7.27 (qd, J = 7.4, 6.4, 2.8 Hz, 4H), 7.06-6.99 (m, 2H), 6.99-6.92 (m, 1H), 6.17 (d, J = 2.5 Hz, 1H), 5.32 (dd, J =12.5, 5.4 Hz, 1H), 4.67-4.54 (m, 1H), 4.52 (dd, J = 9.0, 4.7 Hz, 1H),4.39 (d, J = 13.3 Hz, 1H), 4.23 (dd, J = 10.4, 2.8 Hz, 1H), 4.12 (q, J =7.4 Hz, 1H), 4.03-3.88 (m, 1H), 3.73-3.64 (m, 1H), 3.42 (s, 3H),3.31-3.16 (m, 1H), 3.10- 2.95 (m, 1H), 2.91 (dd, J = 17.4, 4.9 Hz, 1H),2.86-2.66 (m, 3H), 2.47 (ddd, J = 15.7, 9.2, 6.6 Hz, 1H), 2.42-2.29 (m,3H), 2.32-2.26 (m, 1H), 2.26-2.06 (m, 4H), 1.97 (dt, J = 14.7, 7.1 Hz,1H), 1.89-1.78 (m, 3H), 1.74-1.56 (m, 4H), 1.40 (m, 4H) H107

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1s,4s)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]methyl]cyclo- hexyl]acetyl]- octahydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N- (diphenylmeth- yl)pentanediamide;trifluoroacetaldehyde 916.80 (300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.86(d, J = 8.4 Hz, 1H), 8.57-8.23 (m, 4H), 7.35-7.28 (m, 11H), 7.11-6.94(m, 2H), 6.90-6.70 (m, 2H), 6.12 (d, J = 8.3 Hz, 1H), 5.36 (dd, J =12.8, 5.4 Hz, 1H), 4.46- 4.41 (m, 4H), 4.22-4.20 (m, 2H), 4.05-2.95 (m,3H), 3.52-3.50 (m, 1H), 3.23-3.20 (m, 1H), 3.05-2.91 (m, 2H), 2.83-2.54(m, 4H), 2.42-1.59 (m, 13H), 1.40 (d, J = 31.4 Hz, 10H) H108

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1r,4r)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]methyl]cyclo- hexyl]acetyl]- octahydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N- (diphenylmeth- yl)pentanediamide trifluoroacetate916.80 (300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H),8.57-8.21 (m, 4H), 7.31 (tdd, J = 13.9, 6.8, 4.2 Hz, 12H), 7.07-6.94 (m,2H), 6.90-6.71 (m, 2H), 6.12 (d, J = 8.3 Hz, 1H), 5.36 (dd, J = 12.8,5.4 Hz, 1H), 4.45 (dq, J = 16.8, 9.2, 8.8 Hz, 4H), 4.29- 3.38 (m, 4H),3.25-2.80 (m, 1H), 2.80-2.56 (m, 4H), 2.48-1.63 (m, 14H), 1.40 (d, J =29.0 Hz, 9H) H109

(2S)-2-amino-N- [[3-(4-[[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl]car- bamoyl)pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]bu- tyl)phenyl]meth-yl]pentanediamide hydrochloride [(M − 1)]⁻ = 746.23 (300 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.93 (t, J = 5.9 Hz, 1H), 8.55 (t, J = 6.0 Hz, 1H),8.30-8.22 (m, 3H), 7.87 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H),7.40 (d, J = 3.7 Hz, 3H), 7.28-7.20 (m, 1H), 7.10-7.08 (m, 4H),6.99-6.94 (m, 1H), 4.59-4.49 (m, 1H), 4.49-4.37 (m, 2H), 4.36-4.31 (m,2H), 4.21 (dd, J = 15.8, 5.0 Hz, 1H), 3.56-3.49 (m, 7H), 2.44 (s, 3H),2.34-2.09 (m, 3H), 2.09- 1.83 (m, 3H), 1.60-1.48 (m, 5H), 0.93 (s, 9H)H110

(2S)-2-[[(2S,11S)- 11-amino-6-[7-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]heptyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-N- (diphenylmeth- yl)pentanediamidehydrochloride 895.55 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.87 (d, J =8.4 Hz, 1H), 8.58-8.27 (m, 3H), 7.49-7.18 (m, 9H), 7.13-6.95 (m, 2H),6.95-6.73 (m, 3H), 6.15-6.00 (m, 1H), 5.35 (dd, J = 12.8, 5.2 Hz, 1H),5.15 (dd, J = 10.8, 3.1 Hz, 1H), 4.48-4.11 (m, 3H), 3.90- 3.66 (m, 4H),3.32 (s, 3H), 3.02 (d, J = 61.9 Hz, 2H), 2.87 (dd, J = 20.5, 14.4 Hz,2H), 2.82-2.57 (m, 4H), 2.33-1.78 (m, 7H), 1.78-1.44 (m, 4H), 1.28 (d, J= 28.1 Hz, 7H) H111

(4S,5R)-4- [[(5S,8S,10aR)-5- Amino-3-[7-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]heptanoyl]-6- oxo-octahydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]-5- [(4-bromophenyl)meth- oxy]hexanamide hydrochloride 893.20, 895.20 (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.50-8.26 (m, 2H), 7.97 (dd, J = 9.5, 3.3 Hz,1H), 7.57-7.49 (m, 2H), 7.29 (dt, J = 8.5, 2.1 Hz, 2H), 7.16 (s, 1H),7.07-6.96 (m, 2H), 6.86 (dt, J = 8.5, 2.1 Hz, 1H), 6.68 (d, J = 25.0 Hz,1H), 6.62-6.53 (m, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.56-4.28 (m,5H), 4.21-4.04 (m, 1H), 3.87-3.46 (m, 4H), 3.41 (p, J = 6.2 Hz, 1H),3.34 (s, 3H), 3.30-3.09 (m, 1H), 2.98-2.84 (m, 1H), 2.77-2.55 (m, 5H),2.47-2.37 (m, 1H), 2.34-1.91 (m, 4H), 1.91-1.43 (m, 6H), 1.43-1.27 (m,4H), 1.06 (d, J = 6.3 Hz, 3H) H112

(4S,5R)-4- [(5S,8S,10aR)-5- Amino-3-[7-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]heptanoyl]-6- oxo-octahydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]-5-(benzyloxy)hexan- amide hydrochloride 815.30 (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 8.58-8.48 (m, 1H), 8.45-8.31 (m, 2H), 8.03-7.96 (m, 1H),7.45-7.22 (m, 5H), 7.16 (s, 1H), 7.06-6.96 (m, 2H), 6.89-6.84 (m, 1H),6.71 (s, 1H), 5.35 (dd, J = 12.7, 5.4 Hz, 1H), 4.57-4.34 (m, 3H),4.32-4.08 (m, 5H), 3.87-3.74 (m, 2H), 3.52-3.43 (m, 2H), 3.33 (s, 3H),3.28-3.05 (m, 2H), 2.98-2.84 (m, 1H), 2.78-2.56 (m, 4H), 2.48-2.39 (m,1H), 2.37-1.65 (m, 6H), 1.64-1.48 (m, 6H), 1.45-1.24 (m, 4H), 1.10 (d, J= 6.3 Hz, 3H) H113

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]methyl)- 2- fluorophenyl]pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth-yl]pyrrolidine-2- carboxamide hydrochloride 881.40 (400 MHz, DMSO-d₆) δ9.03 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.02 (s, 2H), 7.82 (d, J = 9.3Hz, 1H), 7.47-7.36 (m, 4H), 7.23 (d, J = 13.1 Hz, 1H), 7.12 (d, J = 7.9Hz, 1H), 6.93 (s, 1H), 4.92 (t, J = 7.1 Hz, 1H), 4.61- 4.36 (m, 5H),3.79 (s, 1H), 3.28 (s, 1H), 2.64-2.58 (m, 3H), 2.46 (s, 3H), 2.39-2.21(m, 4H), 2.15 (s, 1H), 2.07-1.96 (m, 1H), 1.84-1.70 (m, 4H), 1.62-1.58(m, 1H), 1.54-1.49 (m, 5H), 1.38 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 6.3Hz, 3H), 0.93 (s, 9H) H114

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 749.45 (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.40(d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 8.0 Hz, 3H),7.39 (d, J = 7.9 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 38.6Hz, 1H), 6.82 (d, J = 7.0 Hz, 3H), 4.91 (q, J = 7.4 Hz, 1H), 4.77 (m,4H), 4.51 (d, J = 8.9 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H), 4.30 (d, J =17.0 Hz, 1H), 4.16 (d, J = 11.1 Hz, 1H), 4.07-3.99 (m, 1H), 3.60 (s,2H), 3.44-2.56 (m, 2H), 2.55 (m, 1H), 2.47 (s, 3H), 2.28-2.18 (m, 3H),2.17-1.98 (m, 2H), 1.95-1.74 (m, 2H), 1.62-1.46 (m, 3H), 1.38 (d, J =7.0 Hz, 3H), 1.31-1.22 (m, 3H), 0.93 (s, 9H) H115

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]methyl)- 3- fluorophenyl]pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide hydrochloride 767.50 (400 MHz, DMSO-d₆) δ9.08 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.15-8.06 (m, 3H), 7.88 (d, J =9.3 Hz, 1H), 7.47-7.37 (m, 6H), 7.05-6.98 (m, 3H), 6.92 (s, 1H),4.63-4.38 (m, 6H), 4.35 (s, 1H), 4.22 (dd, J = 15.9, 5.2 Hz 1H)3.88-3.72 (m, 1H), 3.72-3.61 (m, 1H), 3.26 (s, 1H), 2.59 (t, J = 7.2 Hz,1H), 2.46 (s, 3H), 2.35-2.23 (m, 3H), 2.18- 2.12 (m, 1H), 2.07-2.02 (m,1H), 1.97-1.85 (m, 1H), 1.80-1.70 (m, 2H), 1.57-1.41 (m, 4H), 1.15 (d, J= 6.3 Hz, 3H), 0.94 (s, 9H) H116

(5S,8S,10aR)-8- [[(1S)-3- carbamoyl-1- (diphenylmethylcar-bamoyl)propyl]car- bamoyl]-3-[8-[2-(1- methyl-2,6- dioxopiperidin-3-yl)-1-oxo-3H- isoindol-4-yl]oct-7- ynoyl]-6-oxo- octahydropyrrolo[l,2-a][1,5]diazocin- 5-aminium trifluoroacetate 899.20 Used in the next stepwithout further purification H117

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[4-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]butanoyl]-6-oxo-octahydropyrrolo[l,2- a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)pentanediamide trifluoroacetate 848.30 (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.84 (dd, J = 8.5, 7.0 Hz, 1H), 8.34-8.29 (m,2H), 8.31 (d, J = 5.7 Hz, 1H), 7.35-7.23 (m, 11H), 6.98 (d, J = 4.6 Hz,2H), 6.91-6.86 (m, 1H), 6.79 (s, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.37(dd, J = 12.4, 5.4 Hz, 1H), 4.51- 4.35 (m, 3H), 4.29-4.19 (m, 1H),4.08-3.95 (m, 1H), 3.82 (d, J = 14.7 Hz, 1H), 3.59 (s, 3H), 3.33-3.13(m, 1H), 3.01-2.83 (m, 4H), 2.77-2.53 (m, 4H), 2.25-2.03 (m, 3H),2.02-1.95 (m, 2H), 1.95-1.85 (m, 4H), 1.83-1.63 (m, 4H) H118

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[6-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]hexanoyl]-6- oxo-octahydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)pentanediamide trifluoroacetate 876.40 (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.84 (t, J = 7.9 Hz, 1H), 8.36-8.28 (m, 2H),7.38-7.27 (m, 8H), 7.26-7.18 (m, 4H), 6.97 (d, J = 4.6 Hz, 2H), 6.88 (d,J = 4.6 Hz, 1H), 6.78 (s, 1H), 6.11 (d, J = 8.2 Hz, 1H), 5.37 (dd, J =12.6, 5.4 Hz, 1H), 4.51-4.35 (m, 4H), 4.25-4.13 (m, 1H), 4.01-3.89 (m,1H), 3.86-3.78 (m, 1H), 3.56 (s, 3H), 3.49- 3.40 (m, 1H), 3.24-3.08 (m,2H), 3.05-2.86 (m, 4H), 2.80-2.59 (m, 4H), 2.46-2.38 (m, 2H), 2.25-1.84(m, 4H), 1.85-1.50 (m, 6H), 1.46-1.39 (m, 2H) H119

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[7-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]heptanoyl]-6- oxo-octahydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)pentanediamide trifluoroacetate 890.40 (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.89-8.82 (m, 1H), 8.36-8.28 (m, 3H),7.36-7.23 (m, 11H), 7.00-6.92 (m, 2H), 6.91-6.83 (m, 1H), 6.82-6.75 (m,1H), 6.16-6.12 (m, 1H), 5.37 (dd, J = 12.5, 5.4 Hz 1H), 4.52-4.34 (m,3H), 4.30-4.14 (m, 1H), 4.02-3.94 (m, 1H), 3.88-3.77 (m, 1H), 3.54 (s,3H), 3.28-3.08 (m, 1H), 2.96-2.84 (m, 3H), 2.75-2.68 (m, 1H), 2.66-2.58(m, 1H), 2.50-2.27 (m, 3H), 2.25-2.17 (m, 1H), 2.14-2.04 (m, 2H),2.03-1.95 (m, 2H), 1.95-1.84 (m, 2H), 1.83-1.66 (m, 4H), 1.62-1.50 (m,4H), 1.49-1.37 (m, 4H) H120

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[9-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-4- yl]nonanoyl]-6- oxo-octahydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth-yl)pentanediamide trifluoroacetate 918.40 (400 MHz, DMSO-d₆) δ 11.10 (s,1H), 8.85 (t, J = 8.0 Hz, 1H), 8.38-8.27 (m, 3H), 7.38-7.21 (m, 11H),6.99-6.91 (m, 2H), 6.91-6.83 (m, 1H), 6.79 (s, 1H), 6.11 (d, J = 8.4 Hz,1H), 5.37 (dd, J = 12.6, 5.4 Hz, 1H), 4.52-4.34 (m, 3H), 4.27-4.15 (m,1H), 4.08-3.93 (m, 1H) 3.88-3.78 (m, 1H), 3.55 (s, 3H), 3.28-3.06 (m,1H), 3.03-2.83 (m, 3H), 2.78-2.69 (m, 1H), 2.67-2.58 (m, 1H), 2.49-2.24(m, 2H), 2.17-2.05 (m, 2H), 2.05-1.85 (m, 4H), 1.85-1.64 (m, 4H),1.64-1.46 (m, 4H), 1.43-1.33 (m, 3H), 1.33-1.27 (m, 6H), 1.26-1.09 (m,1H) H121

(2S,4R)-1-[(2S)-2- [([3-[4-([[(2R,3S)- 3-amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]propyl]car- bamoyl)amino]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5- yl)phenyl]meth-yl]pyrrolidine-2- carboxamide trifluoroacetate 750.60 (400 MHz, DMSO-d₆)δ 5 9.01 (d, J = 5.3 Hz, 1H), 7.50-7.41 (m, 4H), 7.29 (dd, J = 8.2, 1.8Hz, 4H), 7.20-7.16 (m, 4H), 6.13 (s, 1H), 4.53 (d, J = 11.6 Hz, 2H),4.49- 4.35 (m, 5H), 3.66-3.64 (m, 1H), 3.33-3.24 (m, 2H), 2.99 (d, J =6.9 Hz, 2H), 2.58 (d, J = 7.8 Hz, 4H), 2.48-2.44 (m, 4H), 2.24 (t, J =7.4 Hz, 4H), 1.75 (q, J = 7.9 Hz, 2H), 1.68-1.64 (m, 4H), 1.14 (s, 3H),0.97 (s, 9H) H122

(2S)-2- [[(5S,8S,10aR)-5- amino-3-(4-[1-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]azetidin-3-yl]butanoyl)-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N- (diphenylmeth- yl)pentanediamide trifluoroacetate903.30 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.84 (dd, J = 10.4, 8.5 Hz,1H), 8.36-8.29 (m, 3H), 7.41-7.19 (m, 11H), 7.07 (d, J = 8.4 Hz, 1H),6.85 (s, 1H), 6.80 (s, 1H), 6.57 (s, 1H), 6.10 (d, J = 8.6 Hz, 1H), 5.35(dd, J = 12.9, 5.3 Hz, 1H), 4.52-4.31 (m, 3H), 4.28- 4.19 (m, 3H), 3.96(d, J = 14.2 Hz, 1H), 3.82-3.74 (m, 2H), 3.49 (d, J = 12.9 Hz, 1H), 3.34(s, 3H), 3.30-3.13 (m, 1H), 3.08- 3.01 (m, 1H), 2.90 (t, J = 14.9 Hz,1H), 2.80 (t, J = 7.4 Hz, 1H), 2.73-2.58 (m, 2H), 2.48-2.30 (m, 2H),2.25-2.09 (m, 2H), 2.04-1.97 (m, 1H), 1.96-1.86 (m, 2H), 1.85-1.62 (m,7H), 1.59-1.37 (m, 3H) H123

(2S)-2- [[(5S,8S,10aR)-5- amino-3-(4-[1-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]piperidin-4-yl]butanoyl)-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N- (diphenylmeth- yl)pentanediamide trifluoroacetate931.30 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.82 (t, J = 8.5 Hz, 1H),8.40-8.24 (m, 3H), 7.38-7.29 (m, 4H), 7.28-7.19 (m, 9H), 7.07 (d, J =8.1 Hz, 1H), 6.77 (s, 1H), 6.09 (d, J = 8.1 Hz, 1H), 5.40-5.30 (m, 1H),4.49- 4.36 (m, 3H), 4.28-4.14 (m, 1H), 4.02-3.90 (m, 2H), 3.85-3.76 (m,1H), 3.57 (s, 3H), 3.16-3.07 (m, 2H), 3.05-2.99 (m, 2H), 2.94-2.86 (m,2H), 2.72-2.57 (m, 2H), 2.25-2.06 (m, 2H), 2.03-1.95 (m, 1H), 1.93-1.78(m, 5H), 1.76-1.68 (m, 4H), 1.65-1.52 (m, 4H), 1.46-1.37 (m, 1H),1.35-1.26 (m, 2H), 1.26-1.21 (m, 1H) H124

(2S)-2-[[(5S,8S,10aR)- 5-amino-3-(6- [[1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-1,3-benzodiazol- 5-yl]amino]hexanoyl)- 6-oxo-octa-hydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]- N-(diphenylmeth- yl)Pentanediamide trifluoroacetate 891.35 (400 MHz, DMSO-d₆) δ 11.16 (s,1H), 8.84 (t, J = 8.4 Hz, 1H), 8.36-8.29 (m, 4H), 7.41-7.13 (m, 14H),6.80 (s, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.43 (dd, J = 12.7, 5.4 Hz, 1H),4.53-4.30 (m, 4H), 4.29-3.74 (m, 3H), 3.38 (s, 3H), 3.32-3.28 (m, 2H),3.28-3.10 (m, 2H), 2.97-2.83 (m, 2H), 2.79-2.57 (m, 2H), 2.48-2.25 (m,2H), 2.25-1.99 (m, 4H), 1.99-1.82 (m, 4H), 1.71-1.47 (m, 4H), 1.43-1.35(m, 2H), 1.26-1.22 (m, 1H) H125

(2S)-2- [[(5S,8S,10aR)-5- amino-3-(4-[4-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]piperazin-1-yl]butanoyl)-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-8-yl]formamido]- N- (diphenylmeth- yl)pentanediamide trifluoroacetate932.75 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.80-8.74 (m, 1H), 8.36-8.30(m, 3H), 7.44-7.14 (m, 11H), 7.01 (d, J = 8.6 Hz, 1H), 6.96-6.90 (m,1H), 6.81-6.74 (m, 1H), 6.73-6.65 (m, 1H), 6.11 (dd, J = 8.3, 2.3 Hz,1H), 5.32 (dd, J = 12.9, 5.4 Hz, 1H), 4.64-4.52 (m, 1H), 4.48-4.27 (m,3H), 4.26-4.22 (m, 2H), 3.92-3.86 (m, 1H), 3.82-3.75 (m, 3H), 3.34 (s,3H), 3.20-3.14 (m, 5H), 3.05-2.82 (m, 3H), 2.77-2.58 (m, 3H), 2.40-2.34(m, 1H), 2.29-2.06 (m, 3H), 2.05-1.88 (m, 5H), 1.87-1.64 (m, 6H) H126

(2S)-2- [[(5S,8S,10aR)-5- amino-3-(3-[4-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]piperazin-1- yl]propanoyl)-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin- 8-yl]formamido]-N-(diphenylmeth- yl)pentanediamide trifluoroacetate 918.70 (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.81-8.58 (m, 2H), 8.45-8.31 (m, 2H),7.60-7.10 (m, 11H), 7.01 (dd, J = 8.7, 1.8 Hz, 1H), 6.93 (dd, J = 4.4,2.2 Hz, 1H), 6.86-6.80 (m, 1H), 6.75-6.64 (m, 1H), 6.11 (d, J = 8.3 Hz,1H), 5.32 (dd, J = 12.9, 5.3 Hz, 1H), 4.66-4.53 (m, 1H), 4.52-4.23 (m,3H), 4.15-3.84 (m, 1H), 3.78 (t, J = 13.3 Hz, 2H), 3.65 (t, J = 13.0 Hz,2H), 3.54- 3.37 (m, 2H), 3.34 (s, 3H), 3.29-3.09 (m, 4H), 2.99-2.79 (m,4H), 2.77-2.56 (m, 2H), 2.35-2.07 (m, 4H), 2.06-1.89 (m, 3H), 1.88-1.80(m, 6H) H127

(2S,4R)-1-[(2S)-2- [9-[(2S)-2-amino-4- carbamoylbu- toxy]non-7-ynamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3-thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride697.30 (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H),8.13-8.09 (m, 2H), 7.87 (d, J = 9.3 Hz, 1H), 7.53-7.29 (m, 4H),6.92-6.89 (m, 1H), 4.59-4.52 (m, 1H), 4.48-4.41 (m, 2H), 4.37-4.35 (m,1H), 4.25 (d, J = 5.2 Hz, 1H), 4.22-4.16 (m, 2H), 3.73-3.63 (m, 2H),3.62-3.56 (m, 4H), 3.52-3.49 (m, 1H), 3.29-2.25 (m, 2H), 2.46 (s, 3H),2.32-2.01 (m, 6H), 1.93-1.89 (m, 1H), 1.78-1.72 (m, 2H), 1.51-1.43 (m,3H), 1.40-1.26 (m, 2H), 0.94 (s, 9H). H128

(2S,4R)-1-[(2S)-2- [(7Z)-9-[(2S)-2- amino-4- carbamoylbu- toxy]non-7-enamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3-thiazol-5-yl)- phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride699.25 (400 MHz, DMSO-d₆) δ 9.16-9.11 (m, 1H), 8.60 (s, 1H), 8.36 (s,1H), 8.13 (s, 2H), 7.86 (d, J = 9.3 Hz, 1H), 7.57-7.28 (m, 5H), 6.91 (s,1H), 5.63-5.38 (m, 7H), 4.54 (d, J = 9.3 Hz, 1H), 4.47-4.38 (m, 2H),4.35 (s, 1H), 4.23 (dd, J = 15.0, 4.8 Hz, 1H), 4.05 (d, J = 5.6 Hz, 1H),3.71- 3.60 (m, 2H), 3.57 (s, 3H), 3.56-3.52 (m, 2H), 3.48-3.33 (m, 1H),3.24 (s, 1H), 2.47- 2.45 (m, 3H), 2.30-2.20 (m, 2H), 2.18-1.96 (m, 3H),1.94-1.87 (m, 1H), 1.83-1.67 (m, 1H), 1.56-1.44 (m, 1H), 1.34-1.22 (m,1H), 0.94 (s, 9H) H129

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 721.55 (400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.43(s, 4H), 7.85 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.40 (d, J= 8.2 Hz, 2H), 7.22 (dd, J = 9.2, 7.2 Hz, 1H), 6.93 (s, 1H), 6.87-6.78(m, 3H), 4.92 (p, J = 6.9 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.44 (t, J= 8.0 Hz, 1H), 4.28 (s, 1H), 4.18 (dd, J = 10.3, 3.6 Hz, 1H), 4.05 (dd,J = 10.4, 6.3 Hz, 1H), 3.48 (s, 1H), 2.54 (s, 2H), 2.48 (s, 3H),2.38-2.22 (m, 2H), 2.20-2.16 (m, 1H), 2.08-1.85 (m, 2H), 1.81-1.78 (s,3H), 1.62- 1.58 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H), 0.95 (s, 9H) H130

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]-2-fluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 767.97 (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.43(d, J = 7.7 Hz, 3H), 7.45 (d, J = 8.3 Hz, 4H), 7.39 (d, J = 8.3 Hz, 2H),7.07-7.03 (m, 2H), 6.94 (s, 1H), 6.91-6.87 (m, 1H), 4.94- 4.90 (m, 1H),4.51 (d, J = 9.4 Hz, 1H), 4.45-4.41 (m, 1H), 4.30-4.26 (m, 1H),4.25-4.20 (m, 1H), 4.17-4.15 (m, 2H), 3.68-3.55 (m, 3H), 2.61-2.57 (m,2H), 2.47 (s, 3H), 2.30-2.26 (m, 2H), 2.08 (s, 1H), 2.17-1.86 (m, 3H),1.84-1.71 (m, 1H), 1.62-1.42 (m, 5H), 1.40-1.36 (m, 3H), 1.33-1.20 (m,2H), 0.93 (s, 9H) H131

(2S,4R)-1-[(2S)-2- (6-[5-[(2S)-2- amino-4- carbamoylbutoxy]- 2-chlorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 783.55 (400 MHz, DMSO-d₆) δ 9.12 (s, 1H),8.45-8.37 (m, 5H), 7.84-7.75 (m, 1H), 7.48-7.29 (m, 5H), 6.98 (d, J =3.0 Hz, 1H), 6.87 (d, J = 8.8, 3.0 Hz, 1H), 4.92 (d, J = 7.3 Hz, 1H),4.52 (d, J = 9.3 Hz, 1H), 4.47- 4.38 (m, 2H), 4.28 (s, 1H), 4.19 (d, J =10.3, 3.6 Hz, 1H), 4.10-4.01 (m, 1H), 3.70- 3.56 (m, 3H), 2.68-2.59 (m,2H), 2.47 (s, 3H), 2.37-2.19 (m, 4H), 2.14-2.10 (m, 1H), 2.04-2.00 (m,1H), 1.92-1.89 (m, 1H), 1.87-1.69 (m, 2H), 1.60 (s, 1H), 1.57-1.44 (m,3H), 1.38 (d, J = 7.0 Hz, 3H), 1.38-1.27 (m, 1H), 1.25-1.21 (m, 1H),0.93 (s, 9H) H132

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 4-chlorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 783.30 (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.39(d, J = 7.8 Hz, 2H), 8.25 (s, 2H), 7.83-7.76 (m, 2H), 7.35-7.32 (m, 2H),7.22 (d, J = 9.9 Hz, 1H), 7.13-7.03 (m, 2H), 6.95 (s, 1H), 6.85-6.83 (m,1H), 4.92-4.90 (m, 2H), 4.52-4.50 (m, 2H), 4.42-4.40 (m, 3H), 4.25-4.21(m, 2H), 4.15-4.13 (m, 1H), 3.67-3.59 (m, 3H), 3.42-3.40 (m, 1H),2.57-2.55 (m, 2H), 2.31-2.29 (m, 1H), 2.16-2.06 (m, 2H), 2.01 (s, 3H),1.94-1.92 (m, 2H), 1.85-1.75 (m, 4H), 1.62-1.51 (m, 2H), 1.47-1.35 (m,1H), 1.27-1.25 (m, 2H), 1.23 (s, 9H) H133

(2S,4R)-1-[(2S)-2- (6-[3-[(3R)-3- amino-5- carbamoylpen-tyl]phenyl]hexan- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- ylpyrrolidine-2-carboxamide hydrochloride 747.60 (300 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.38(d, J = 7.7 Hz, 1H), 8.17 (s, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.41 (q, J= 8.4 Hz, 4H), 7.18 (t, J = 7.4 Hz, 1H), 7.11-6.96 (m, 3H), 6.89 (s,1H), 4.90 (d, J = 7.3 Hz, 1H), 4.50 (d, J = 9.4 Hz, 1H), 4.42 (t, J =8.0 Hz, 1H), 4.27 (s, 1H), 3.62-3.58 (m, 3H), 3.08 (s, 1H), 2.68-2.57(m, 2H), 2.56-2.53 (m, 1H), 2.46 (s, 3H), 2.34-1.95 (m, 4H), 1.91-1.74(m, 6H), 1.57-1.42 (m, 4H), 1.43-1.24 (m, 4H), 1.32-1.24 (m, 2H), 0.92(s, 9H) H134

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]-5-chlorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 783.20 (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.42(d, J = 6.9 Hz, 3H), 7.79 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H),7.40 (d, J = 8.3 Hz, 2H), 7.12 (s, 2H), 6.90 (d, J = 1.9 Hz, 2H), 6.82(t, J = 1.8 Hz, 1H), 4.98-4.85 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H),4.47-4.39 (m, 1H), 4.31-4.26 (m, 1H), 4.24-4.18 (m, 1H), 4.12-4.04 (m,1H), 3.61 (d, J = 4.4 Hz, 2H), 2.48 (s, 3H), 2.38-2.20 (m, 3H), 2.18-2.07 (m, 1H), 2.03 (t, J = 10.9 Hz, 1H), 1.98-1.87 (m, 1H), 1.83-1.68(m, 1H), 1.60 (s, 3H), 1.58-1.44 (m, 4H), 1.38 (d, J = 7.0 Hz, 3H),1.32-1.21 (m, 3H), 1.14- 1.02 (m, 1H), 0.93 (s, 9H) H135

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-methylphenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 763.35 (400 MHz, DMSO-d₆) δ 9.09 (s, 1H),8.50- 8.28 (m, 3H), 7.80 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H),7.39 (d, J = 8.3 Hz, 2H), 7.07 (t, J = 7.9 Hz, 1H), 6.93 (s, 1H),6.82-6.74 (m, 2H), 4.96-4.89 (m, 1H), 4.55-4.49 (m, 1H), 4.43 (t, J =8.0 Hz, 1H), 4.28 (s, 1H), 4.14 (dd, J = 10.4, 3.5 Hz, 1H), 4.02 (dd, J= 10.4, 5.6 Hz, 1H), 3.64- 3.58 (m, 6H), 3.53-3.49 (m, 1H), 2.57-2.53(m, 1H), 2.47 (s, 3H), 2.35-2.23 (m, 2H), 2.17 (s, 3H), 2.14-1.87 (m,3H), 1.84-1.71 (m, 4H), 1.57-1.44 (m, 3H), 1.38 (d, J = 7.0 Hz, 3H),1.35-1.13 (m, 1H), 0.94 (s, 9H) H136

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl]hexan- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]cyclopro- pyl]pyrrolidine-2-carboxamide hydrochloride 761.55 (400 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.83(s, 1H), 8.38-8.34 (m, 2H), 7.90 (d, J = 9.3 Hz, 1H), 7.37-7.27 (m, 4H),7.21 (t, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.86-6.77 (m, 2H), 4.55 (d, J =9.4 Hz, 1H), 4.39 (dd, J = 17.1, 8.9 Hz, 2H), 4.17 (dd, J = 10.3, 3.6Hz, 1H), 4.04 (dd, J = 10.4, 6.4 Hz, 1H), 3.61 (d, J = 5.8 Hz, 3H), 2.56(d, J = 7.8 Hz, 2H), 2.45 (s, 3H), 2.39-2.22 (m, 2H), 2.14 (dt, J =14.2, 7.2 Hz, 1H), 2.05-1.81 (m, 2H), 1.78-1.74 (m, 5H), 1.60 (s, 3H),1.53- 1.49 (m, 1H), 1.27-1.23 (m, 6H), 1.17-1.09 (m, 1H), 0.94 (s, 9H)H137

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 4-fluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 767.35 (400 MHz, DMSO-d₆) δ 6 9.08 (s, 1H),8.41 (d, J = 7.7 Hz, 1H), 8.35-8.32 (m, 3H), 7.80 (d, J = 9.3 Hz, 1H),7.48-7.32 (m, 5H), 7.17-7.04 (m, 2H), 6.94 (s, 1H), 4.96-4.88 (m, 2H),4.52 (d, J = 9.1 Hz, 1H), 4.43 (d, J = 8.0 Hz, 1H), 4.31-4.20 (m, 2H),4.15 (d, J = 8.3 Hz, 1H), 3.69-3.56 (m, 6H), 3.54- 3.50 (m, 1H), 2.47(s, 3H), 2.29-2.25 (m, 2H), 2.14-2.10 (m, 1H), 2.04-2.00 (m, 1H),1.95-1.91 (m, 1H), 1.79-1.75 (m, 2H), 1.57-1.53 (m, 4H), 1.38 (d, J =7.0 Hz, 3H), 1.25 (m, 1H), 0.93 (d, 9H) H138

(2S)-2-amino-N-[3- (5-[[(2S)-1- [(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pen- tyl)phenyl]pentane-diamide hydrochloride 762.45 (300 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.04(s, 1H), 8.47-8.36 (m, 4H), 7.76 (d, J = 9.2 Hz, 1H), 7.49-7.36 (m, 7H),7.24 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.6 Hz, 2H), 4.94-4.88 (m, 1H),4.57-4.36 (m, 2H), 4.27 (s, 1H), 4.03 (s, 1H), 2.57-2.55 (m, 1H), 2.46(s, 3H), 2.28-2.20 (m, 3H), 2.16-1.97 (m, 4H), 1.83-1.74 (m, 1H),1.64-1.43 (m, 6H), 1.37 (d, J = 6.7 Hz, 3H), 1.33-1.20 (m, 3H), 0.92 (s,9H) H139

(2S,4R)-1-[(2S)-2- [6-(3-[[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]phenyl)hexan- amido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3- thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamide749.30 (300 MHz, DMSO-d₆) δ 6 9.04 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H),8.21 (s, 3H), 7.85 (d, J = 9.3 Hz, 1H), 7.49-7.39 (m, 6H), 7.21 (t, J =7.7 Hz, 1H), 6.96 (s, 1H), 6.89-6.78 (m, 4H), 4.55 (d, J = 9.3 Hz, 1H),4.51-4.33 (m, 3H), 4.24 (dd, J = 15.9, 5.4 Hz, 1H), 3.73- 3.63 (m, 2H),3.40 (q, J = 7.0 Hz, 2H), 2.47 (s, 3H), 2.37-2.24 (m, 3H), 2.20-1.81 (m,4H), 1.62-1.49 (m, 5H), 1.34-1.28 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H),1.11 (t, J = 7.0 Hz, 1H), 0.95 (s, 9H) H140

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl]pentan- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 735.35 (400 MHz, DMSO-d₆) δ 9.12 (d, J = 1.5Hz, 1H), 8.36 (s, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.49-7.37 (m, 4H), 7.22(t, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.81 (d, J = 8.8 Hz, 3H), 4.92 (p, J= 7.1 Hz, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28(s, 1H), 4.19-4.15 (m, 1H), 4.05-4.01 (m, 1H), 3.69-3.60 (m, 1H),3.52-3.36 (m, 1H), 2.57-2.53 (m, 1H), 2.47 (s, 3H), 2.32-2.28 (m, 2H),2.18-2.14 (m, 1H), 2.07-2.03 (m, 1H), 1.92-1.88 (m, 2H), 1.82-1.69 (m,6H), 1.62-1.58 (m, 2H), 1.58-1.43 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H),1.26-1.22(m, 1H), 0.94 (s, 9H) H141

(2S,4R)-1-[(2S)-2- (6-[5-[(2S)-2- amino-4- carbamoylbutoxy]- 2-methylphenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 763.35 crude used next step withoutpurification H142

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 5-methylphenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 763.35 crude used next step withoutpurification H143

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 4-methylphenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 763.35 (400 MHz, Chloroform-d) δ 8.70 (s, 1H),7.41-7.30 (m, 5H), 7.03 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.5, 1.5 Hz,1H), 6.61 (d, J = 1.6 Hz, 1H), 6.52-6.47 (m, 1H), 6.36 (d, J = 8.7 Hz,1H), 5.75 (s, 1H), 5.32 (s, 1H), 5.10 (d, J = 14.9, 7.4 Hz, 2H), 4.73(s, 1H), 4.58 (d, J = 8.8 Hz, 1H), 4.55-4.51 (m, 1H), 4.13-3.94 (m, 4H),3.63 (d, J = 11.3, 3.8 Hz, 1H), 3.50 (s, 1H), 2.56-2.52 (m, 4H), 2.36(d, J = 6.8, 2.2 Hz, 2H), 2.19-2.10 (m, 3H), 2.03-1.99 (m, 2H),1.62-1.59 (m, 3H), 1.51-1.47 (m, 3H), 1.46-1.40 (m, 5H), 1.29-1.25 (m,3H), 1.04 (s, 9H) H144

(2S,4R)-1-[(2S)-2- (6-[5-[(2S)-2- amino-4- carbamoylbutoxy]- 2-fluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 767.35 (400 MHz, DMSO-d₆) δ 9.29 (s, 1H), 8.46(s, 3H), 7.80 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 8.3, 2.1 Hz, 2H),7.44-7.33 (m, 2H), 7.06 (t, J = 9.2 Hz, 1H), 6.91 (dd, J = 6.3, 3.1 Hz,1H), 6.84 (dd, J = 8.8, 3.8 Hz, 1H), 4.98-4.86 (m, 1H), 4.51 (d, J = 9.3Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 4.21- 4.12 (m, 1H),4.04 (dd, J = 10.3, 6.3 Hz, 1H), 3.45 (s, 2H), 2.55 (t, J = 7.6 Hz, 2H),2.45 (s, 3H), 2.31-2.27 (m, 3H), 2.18-2.01 (m, 1H), 2.00-1.85 (m, 2H),1.83-1.77 (m, 1H), 1.59 (s, 3H), 1.57-1.44 (m, 6H), 1.37 (d, J = 7.0 Hz,3H), 1.33-1.21 (m, 2H), 0.93 (s, 9H) H145

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 5-fluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 767.30 (400 MHz, DMSO-d₆) δ 9.22 (s, 1H),8.45- 8.41 (m, 3H), 7.80 (d, J = 9.3 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H),7.40 (d, J = 8.1 Hz, 2H), 6.72-6.63 (m, 3H), 4.94-4.90 (m, 1H), 4.51 (d,J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.30-4.16 (m, 1H), 4.16-4.03(m, 1H), 3.62-3.58 (m, 6H), 2.55 (d, J = 7.6 Hz, 1H), 2.48 (s, 3H),2.31-2.27 (m, 2H), 2.18-2.01 (m, 1H), 1.94-1.90 (m, 1H), 1.82-1.70 (m,9H), 1.61-1.57 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H), 1.27-1.23 (m, 1H),0.93 (s, 9H) H146

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]methyl)- 2- methylphenyl]pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth-yl]pyrrolidine-2- carboxamide hydrochloride 777.05 (400 MHz, DMSO-d₆) δ9.03 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.03-7.98 (m, 3H), 7.82 (d, J =9.4 Hz, 1H), 7.45 (d, J = 8.1 Hz, 3H), 7.39 (d, J = 8.3 Hz, 2H),7.16-7.06 (m, 4H), 6.93 (s, 1H), 4.92 (t, J = 7.2 Hz, 1H), 4.54-4.36 (m,3H), 4.28 (s, 1H), 3.79-3.70 (m, 1H), 3.64-3.60 (m, 2H), 3.27 (s, 1H),2.57-2.54 (m, 1H), 2.46 (s, 3H), 2.36-2.29 (m, 1H), 2.26-2.23 (m, 5H),2.20-2.10 (m, 1H), 2.05-1.99 (m, 1H), 1.85-1.67 (m, 3H), 1.57-1.46 (m,5H), 1.38 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H), 0.94 (s, 9H)H147

(2S,4R)-1-((S)-2- (6-(3-(((2R,3S)-3,6- diamino-6- oxohexan-2-yl)oxy)phenyl)hexan- amido)-3,3- dimethylbutanoyl)- 4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)eth- yl)pyrrolidine-2- carboxamidehydrochloride 763.35 (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.42 (d, J = 7.8Hz, 1H), 8.35-8.30 (m, 3H), 7.80 (d, J = 9.2 Hz, 1H), 7.48-7.36 (m, 4H),7.20 (t, J = 7.8 Hz, 1H), 6.96 (s, 1H), 6.89-6.77 (m, 3H), 4.96-4.88 (m,1H), 4.74-4.69 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz,1H), 4.28 (s, 1H), 3.64-3.58 (m, 4H), 3.42-3.30 (m, 1H), 2.47 (s, 3H),2.39- 2.17 (m, 4H), 2.17-1.97 (m, 2H), 1.97-1.69 (m, 3H), 1.64-1.42 (m,5H), 1.38 (d, J = 7.0 Hz, 3H), 1.13-1.27 (m, 1H), 1.23 (d, J = 6.3 Hz,3H), 0.93 (s, 9H) H148

(2S)-2-amino-N- [[3-(5-[[(2S)-1- [(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pen- tyl)phenyl]meth-yl]pentanediamide hydrochloride 776.55 crude used next step withoutpurification H149

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl[pentan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3- thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamidehydrochloride 721.45 (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 8.99-8.94 (m,2H), 8.87 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H),7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.42-7.39 (m,3H), 7.24 (s, 1H), 7.19-7.15 (m, 1H), 7.11-7.08 (m, 1H), 6.99 (t, J =7.5 Hz, 1H), 6.79-6.69 (m, 1H), 5.09 (dd, J = 10.7, 2.9 Hz, 1H), 4.69(t, J = 9.4 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H), 4.48- 4.39 (m, 2H), 4.35(s, 1H), 4.22 (dd, J = 15.8, 5.4 Hz, 1H), 4.02-3.96 (m, 1H), 3.92- 3.88(m, 2H), 3.70-3.61 (m, 2H), 2.88 (d, J = 16.6 Hz, 1H), 2.45 (s, 3H),2.35-2.33 (m, 1H), 2.32-1.96 (m, 4H), 1.96-1.61 (m, 3H), 1.57-1.47 (m,3H), 0.94 (s, 9H) H150

(2S)-2-amino-N- [[3-(5-[[(2S)-1- [(2S,4R)-4- hydroxy-2-([[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl]car- bamoyl)pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]pen- tyl)phenyl]meth-yl]pentanediamide hydrochloride 762.50 (400 MHz, DMSO-d₆) δ 9.06 (s,1H), 9.02 (t, J = 5.8 Hz, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.36 (d, J =14.9 Hz, 2H), 7.85 (d, J = 9.3 Hz, 1H), 7.46-7.38 (m, 4H), 7.24 (t, J =7.5 Hz, 1H), 7.14-7.07 (m, 2H), 6.95 (s, 1H) 4.54 (d J = 9.2 Hz 1H)4.48-4.38 (m 1H), 4.33 (dd, J = 11.7, 7.1 Hz, 2H), 4.27- 4.18 (m, 1H),3.93-3.75 (m, 1H), 3.70-3.60 (m, 2H), 2.57-2.54 (m, 2H), 2.46 (s, 3H),2.34-2.18 (m, 2H), 2.17-1.86 (m, 4H), 1.61-1.45 (m, 4H), 1.27 (dd, J =14.4, 7.0 Hz, 2H), 0.94 (s, 9H). H151

(2S,4R)-1-[(2S)-2- [(1-[3-[4- ([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]propyl]cyclo- propyl)formamido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4- (4-methyl-1,3- thiazol-5-yl)phenyl]meth- yl]pyrrolidine-2- carboxamide hydrochloride 775.50 crudeused next step without purification H152

(2S,4R)-1-[(2S)-2- (6-[3-[(3R)-3- amino-5- carbamoylpen-tyl]phenyl]hexan- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3- thiazol-5- yl)phenyl]meth- yl]pyrrolidine-2- carboxamidehydrochloride 733.30 (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.60 (t, J = 6.0Hz, 1H), 8.22 (s, 2H), 7.85 (d, J = 9.3 Hz, 1H), 7.46-7.38 (m, 4H), 7.19(t, J = 7.5 Hz, 1H), 7.03 (dd, J = 12.4, 5.3 Hz, 3H), 6.04-5.98 (m, 1H),4.54 (d, J = 9.4 Hz, 1H), 4.48-4.38 (m, 2H), 4.36 (s, 1H), 4.23 (dd, J =15.9, 5.3 Hz, 1H), 3.72-3.60 (m, 2H), 3.39 (q, J = 7.0 Hz, 1H) 3.08 (s,1H), 2.69-2.58 (m, 2H), 2.46 (s, 3H), 2.33-2.18 (m, 3H), 2.17-2.10 (m,1H), 2.05 (t, J = 10.4 Hz, 1H), 1.96-1.88 (m, 1H), 1.87-1.80 (m, 4H),1.62-1.43 (m, 5H), 1.33-1.21 (m, 2H), 1.09 (t, J = 7.0 Hz, 2H), 0.93 (s,9H) H153

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]methyl)- 3- fluorophenyl]pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth-yl]pyrrolidine-2- carboxamide hydrochloride 781.50 (400 MHz, DMSO-d₆) δ9.09 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.14-8.07 (m, 3H), 7.83 (d, J =9.3 Hz, 1H), 7.49-7.36 (m, 6H), 7.04-7.01 (m, 2H), 6.92 (s, 1H),4.95-4.90 (m, 1H), 4.63-4.46 (m, 3H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s,1H), 3.84-3.79 (m, 1H), 3.66-3.59 (m, 2H), 3.26 (s, 1H), 2.59 (t, J =7.2 Hz, 1H), 2.47 (s, 3H), 2.36-2.20 (m, 3H), 2.20-2.09 (m, 1H),2.05-2.00 (m, 1H), 1.85-1.68 (m, 4H), 1.58-1.41 (m, 4H), 1.38 (d, J =7.0 Hz, 3H), 1.16 (d, J = 6.3 Hz, 3H), 0.94 (s, 9H) H154

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan-2-yl]oxy]methyl)- 3- methylphenyl]pentan- amido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth-yl]pyrrolidine-2- carboxamide hydrochloride 777.30 (400 MHz, DMSO-d₆) δ9.18 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 10.9 Hz, 2H), 7.82(d, J = 9.2 Hz, 1H), 7.48-7.44 (m, 3H), 7.40 (d, J = 8.3 Hz, 2H), 7.27(d, J = 7.6 Hz, 2H), 6.99-6.97 (d, J = 10.0 Hz, 3H), 4.92 (p, J = 6.9Hz, 1H), 4.52 (dd, J = 10.5, 5.3 Hz, 2H), 4.46-4.40 (m, 2H), 4.29- 4.27(m, 1H), 3.87-3.72 (m, 2H), 3.38 (q, J = 7.0 Hz, 1H), 3.26-3.24 (m, 1H),2.48 (s, 3H), 2.34-2.24 (m, 4H), 2.15 (dd, J = 13.5, 6.4 Hz, 1H), 2.02(t, J = 10.3 Hz, 1H), 1.82- 1.75 (m, 3H), 1.60 (s, 3H), 1.52 (s, 3H),1.38 (d, J = 7.0 Hz, 3H), 1.16 (d, J = 6.3 Hz, 3H), 1.09 (t, J = 7.0 Hz,2H), 0.94 (s, 9H) H155

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- amino-5- carbamoylpentan- 2-yl]oxy]meth- yl)phenyl]pentan- amido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[4-(4- methyl-1,3-thiazol- 5- yl)phenoxy]pyr- rolidine-2-carboxamide hydrochloride 751.55 (400 MHz, Methanol-d₄) δ 9.90 (d, J =8.1 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.31(d, J = 7.7 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 4.64 (t, J = 5.9 Hz, 2H),4.57 (s, 1H), 4.52 (d, J = 11.6 Hz, 1H), 3.96 (d, J = 11.0 Hz, 1H), 3.83(t, J = 6.2 Hz, 2H), 3.72-3.66 (m, 6H), 3.36-3.34 (m, 1H) 2.66 (s, 1H),2.60 (s, 2H), 2.49-2.40 (m, 2H), 2.30 (d, J = 18.7 Hz, 2H), 1.90 (m,2H), 1.66 (s, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.05 (s, 9H) H156

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-fluorophenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 739.20 (400 MHz, DMSO-d₆) δ 9.04-9.02 (m, 1H),8.40 (d, J = 7.8 Hz, 1H), 8.36-8.33 (m, 1H), 8.32-8.27 (m, 2H), 7.89 (d,J = 9.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H),7.09-7.05 (m, 2H), 6.98-6.95 (m, 1H), 6.92-6.86 (m, 1H), 4.92-4.91 (m,2H), 4.53 (d, J = 9.3 Hz, 1H), 4.44-4.42 (m, 1H), 4.32-4.28 (m, 1H),4.25-4.21 (m, 1H), 4.15-4.11 (m, 1H), 3.62-3.60 (m, 2H), 2.63-2.58 (m,2H), 2.50-2.45 (m, 3H), 2.31-2.28 (m, 4H), 2.21-2.18 (m, 1H), 2.04-2.02(m, 1H), 1.93-1.90 (m, 2H), 1.85-1.72 (m, 4H), 1.38 (d, J = 7.0 Hz, 3H),0.95 (s, 9H) H157

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-fluoro-5-methylphenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 753.35 (400 MHz, DMSO-d₆) δ 9.12 (s, 1H),8.48- 8.34 (m, 3H), 7.87 (d, J = 9.2 Hz, 1H), 7.48-7.37 (m, 5H),7.00-6.84 (m, 2H), 6.67 (d, J = 5.9 Hz, 1H), 4.96-4.88 (m, 1H), 4.53 (d,J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.24-4.17 (m,1H), 4.17-4.09 (m, 1H), 2.60-2.53 (m, 2H), 2.47 (s, 3H), 2.37-2.28 (m,2H), 2.26 (s, 3H), 2.22-2.12 (m, 1H), 2.07-1.98 (m, 1H), 1.91 (q, J =6.9 Hz, 2H), 1.81-1.72 (m, 8H), 1.38 (s, 3H), 0.95 (s, 9H) H158

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-fluoro-5-methylphenyl]pentan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 767.40 (300 MHz, DMSO-d₆) δ 9.07 (s, 1H),8.42- 8.32 (m, 3H), 7.80 (d, J = 9.3 Hz, 1H), 7.50-7.40 (m, 3H),7.40-7.27 (m, 2H), 6.99-6.80 (m, 2H), 6.72-6.64 (m, 1H), 4.91 (p, J =7.2 Hz, 1H), 4.50 (d, J = 9.2 Hz, 1H), 4.41 (t, J = 8.0 Hz, 1H), 4.27(s, 1H), 4.19 (dd, J = 10.6, 3.6 Hz, 1H), 4.10 (dd, J = 10.6, 6.1 Hz,1H), 2.46 (s, 3H), 2.36-2.28 (m, 2H), 2.24 (s, 3H), 2.22-2.08 (m, 2H),2.06-1.83 (m, 4H), 1.78-1.71 (m, 5H), 1.54-1.45 (m, 5H), 1.37 (s, 3H),0.92 (s, 9H) H159

(2S,4R)-1-[(2S)-2- (5-[4-[(4R)-4- amino-6- carbamoylhex-yl]phenyl]pentan- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 747.45 (300 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.40(d, J = 7.7 Hz, 1H), 8.02-7.78 (m, 4H), 7.53-7.31 (m, 5H), 7.12 (s, 4H),4.99-4.88 (m, 1H), 4.55-4.38 (m, 2H), 4.30 (s, 1H), 3.18-3.01 (m, 2H),2.50-2.37 (m, 5H), 2.35-1.97 (m, 6H), 1.90-1.69 (m, 4H), 1.69-1.45 (m,10H), 1.39 (d, J = 6.9 Hz, 3H), 0.95 (s, 9H) H160

(2S,4R)-1-[(2S)-2- (6-[6-[(1S)-1- amino-3- carbamoylpro- pyl]pyridin-3-yl]hexanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 720.45 (300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 9.07(s, 3H), 9.02-9.01 (d, J = 2.0 Hz, 1H), 8.76-8.73 (dd, J = 8.4, 2.0 Hz,1H), 8.46- 8.44 (d, J = 7.8 Hz, 1H), 8.08-8.06 (d, J = 8.4 Hz, 1H),7.85-7.83 (d, J = 9.3 Hz, 1H), 7.50-7.44 (d, J = 8.1 Hz, 2H), 7.41-7.36(d, J = 8.3 Hz, 2H), 6.85 (s, 1H), 4.96-4.88 (m, 1H), 4.58 (s, 1H),4.53-4.51 (d, J = 9.4 Hz, 1H), 4.45-4.41 (t, J = 8.1 Hz, 1H), 4.29- 4.27(m, 1H), 3.61-3.60 (d, J = 3.3 Hz, 2H), 3.57 (s, 7H), 3.08-3.05 (t, J =7.8 Hz, 2H), 2.47 (s, 3H), 2.36-2.11 (m, 2H), 2.08- 1.97 (m, 2H),1.80-1.75 (m, 3H), 1.62-1.44 (m, 2H), 1.39 (s, 1H), 1.37 (s, 1H), 0.94(s, 9H) H161

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- amino-4- carbamoylbutoxy]-2-chlorophenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 755.30 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.40(d, J = 7.9 Hz, 1H), 8.27 (s, 2H), 7.89 (d, J = 9.1 Hz, 1H), 7.45 (d, J= 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.26 (t, J = 7.9 Hz, 1H), 7.06(d, J = 8.1 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.96-4.88 (m, 1H),4.71-4.60 (m, 1H), 4.57-4.49 (m, 1H), 4.43 (t, J = 7.9 Hz, 1H), 4.28 (s,1H), 4.26-4.17 (m, 1H), 4.15-4.11 (m, 1H), 3.76-3.63 (m, 1H), 3.60 (d, J= 3.6 Hz, 2H), 3.53-3.45 (m, 1H), 3.46-3.37 (m, 1H), 2.71 (d, J = 7.8Hz, 1H), 2.46 (s, 3H), 2.32-2.28 (m, 1H), 2.22-2.18 (m, 1H), 1.99-1.95(m, 2H), 1.84-1.75 (m, 4H), 1.68-1.58 (m, 1H), 1.55-1.45 (m, 1H), 1.38(d, J = 7.0 Hz, 3H), 1.24 (s, 1H), 0.95 (s, 9H) H162

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- amino-4- carbamoylbutoxy]-2-chlorophenyl]pentan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 769.25 (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.41(d, J = 7.7 Hz, 1H), 8.36 (s, 2H), 7.84 (d, J = 9.3 Hz, 1H), 7.45 (d, J= 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.05(dd, J = 8.3, 1.4 Hz, 1H), 7.02- 6.96 (m, 1H), 4.93 (p, J = 7.0 Hz, 1H),4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.31-4.20 (m, 1H),4.15 (dd, J = 10.5, 5.6 Hz, 1H), 3.69-3.57 (m, 3H), 2.70 (d, J = 7.1 Hz,2H), 2.47 (s, 3H), 2.41-2.23 (m, 2H), 2.23-2.11 (m, 1H), 2.07-1.91 (m,4H), 1.85-1.72 (m, 3H), 1.63-1.60 (m, 1H), 1.59-1.51 (m, 5H), 1.38 (d, J= 7.0 Hz, 3H), 0.94 (s, 9H) H163

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 5-chloro-2-fluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 801.35 used next step directly withoutpurification H164

2-amino-N-[2- chloro-3-(4-[[(2S)- 1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]bu- tyl)phenyl]pentane-diamide hydrochloride 782.25 (300 MHz, DMSO-d₆) δ 10.23 (s, 1H), 9.04(s, 1H), 8.45 (s, 2H), 8.38 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 9.2 Hz,1H), 7.61 (dd, J = 11.4, 7.0 Hz, 1H), 7.60-7.42 (m, 2H), 7.45-7.26 (m,2H), 7.29-7.16 (m, 1H), 6.96 (s, 1H), 4.91 (t, J = 7.2 Hz, 1H), 4.51 (d,J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 4.17 (s, 1H),3.68-3.58 (m, 4H), 2.74-2.70 (m, 2H), 2.45 (s, 3H), 2.34-2.30 (m, 3H),2.22-2.03 (m, 3H), 2.01-1.97 (m, 1H), 1.86-1.71 (m, 2H), 1.56-1.52 (m,4H), 1.37 (d, J = 7.0 Hz, 3H), 0.93 (s, 9H) H165

(2S)-2-amino-N-[2- chloro-3-(3-[[(2S)- 1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pro- pyl)phenyl]pentane-diamide hydrochloride 768.25 (400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 9.03(s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.53 (d, J= 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.27 (s, 2H), 7.15 (s, 2H),6.99 (s, 1H), 4.93 (p, J = 7.3 Hz, 1H), 4.54 (d, J = 9.2 Hz, 1H), 4.43(t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.17 (d, J = 6.5 Hz, 1H), 3.67-3.58(m, 1H), 2.72 (t, J = 7.3 Hz, 2H), 2.47 (s, 3H), 2.33 (q, J = 7.4 Hz,3H), 2.23-2.19 (m, 1H), 2.10-2.06 (m, 3H), 1.80-1.76 (m, 4H), 1.85-1.73(m, 2H), 1.62-1.58 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H), 0.95 (s, 9H) H166

(2S)-2-amino-N-[3- (3-[[(2S)-1- [(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pro- pyl)phenyl]pentane-diamide hydrochloride 734.30 (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.03(s, 1H), 8.49 (s, 3H), 8.15 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.56-7.46(m, 3H), 7.44 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.25 (t, J= 7.8 Hz, 1H), 6.94 (d, J = 7.2 Hz, 2H), 4.92 (p, J = 7.2 Hz, 1H), 4.53(d, J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28-3.61 (m, 3H),2.54-2.51 (m, 1H), 2.46 (s, 3H), 2.34-2.14 (m, 4H), 2.12-1.98 (m, 4H),1.79-1.75 (m, 4H), 1.38-1.33 (m, 3H), 0.95 (s, 9H) H167

(2S)-2-amino-N-[2- chloro-3-(5-[[(2S)- 1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pen- tyl)phenyl]pentane-diamide hydrochloride 796.35 (300 MHz, DMSO-d₆) δ 10.30 (s, 1H), 9.10(s, 1H), 8.61-8.32 (m, 5H), 7.82 (d, J = 9.1 Hz, 1H), 7.54-7.39 (m, 6H),7.34- 7.22 (m, 2H), 6.99 (s, 1H), 4.93 (t, J = 7.2 Hz, 1H), 4.53 (d, J =9.2 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.30 (s, 1H), 4.23-4.17 (m, 2H),3.62 (s, 2H), 2.73 (t, J = 7.8 Hz, 2H), 2.48 (s, 3H), 2.41-2.22 (m, 2H),2.21-1.98 (m, 4H), 1.84-1.77 (m, 1H), 1.66-1.44 (m, 4H), 1.39 (d, J =6.9 Hz, 3H), 1.36-1.19 (m, 1H), 0.95 (s, 9H) H168

(2S)-2-amino-N-[2- fluoro-3-(5-[[(2S)- 1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pen- tyl)phenyl]pentane-diamide hydrochloride 780.40 (300 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.09(s, 1H), 8.57-8.35 (m, 4H), 7.81 (d, J = 9.3 Hz, 1H), 7.73-7.68 (m, 1H),7.55 (s, 1H), 7.43 (q, J = 8.3 Hz, 4H), 7.12 (d, J = 6.4 Hz, 2H), 6.99(s, 1H), 4.98-4.88 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.0Hz, 1H), 4.29 (s, 1H), 4.17 (s, 1H), 2.62 (t, J = 7.4 Hz, 2H), 2.48 (s,3H), 2.34-2.23 (m, 3H), 2.19-1.97 (m, 5H), 1.88-1.72 (m, 1H), 1.65-1.44(m, 5H), 1.39 (d, J = 7.0 Hz, 3H), 1.35-1.18 (m, 2H), 0.94 (s, 9H) H169

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-fluoro-6-methylphenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 781.35 (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.41(d, J = 7.8 Hz, 1H), 8.33 (s, 2H), 7.81 (d, J = 9.2 Hz, 1H), 7.48-7.42(m, 2H), 7.42- 7.32 (m, 2H), 6.94 (d, J = 6.7 Hz, 2H), 4.92 (p, J = 7.3Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s,1H), 4.18 (dd, J = 10.5, 3.6 Hz, 1H), 4.11-4.07 (m, 1H), 3.67-3.60 (m,2H), 2.65-2.53 (m, 2H), 2.47 (s, 3H), 2.39-2.26 (m, 2H), 2.23 (s, 3H),2.18-1.97 (m, 2H), 1.96-1.85 (m, 2H), 1.85-1.76 (m, 2H), 1.75-1.71 (m,1H), 1.60 (s, 3H), 1.55-1.42 (m, 5H), 1.41-1.27 (m, 4H), 0.93 (s, 9H)H170

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2,6-difluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 785.35 (400 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.41(s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.48-7.37 (m, 4H), 7.37-7.31 (m, 1H),7.13 (td, J = 9.3, 5.3 Hz, 1H), 7.01 (td, J = 9.2, 1.8 Hz, 1H), 6.94 (s,1H), 4.92 (p, J = 7.1 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (t, J =8.0 Hz, 1H), 4.28 (s, 1H), 4.22 (dd, J = 10.4, 3.6 Hz, 1H), 4.14 (dd, J= 10.5, 6.1 Hz, 1H), 3.67-3.60 (m, 2H), 2.61 (s, 2H), 2.47 (s, 3H),2.39-2.20 (m, 3H), 2.16-1.98 (m, 1H), 1.98-1.84 (m, 2H), 1.81-1.78 (m,2H), 1.60 (s, 3H), 1.54-1.44 (m, 5H), 1.38 (d, J = 6.9 Hz, 3H),1.30-1.26 (m, 2H), 0.92 (s, 9H) H171

4-[3-[(2-amino-4- carbamoylbutyl)(meth- yl)amino]-2- fluorophenyl]butylN-[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl]car- bamoyl]pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamate hydrochloride 782.35 (400 MHz, DMSO-d₆) δ9.14 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.15 (s, 2H), 7.50-7.33 (m, 4H),7.06-6.94 (m, 2H), 6.95-6.84 (m, 2H), 4.91 (p, J = 7.1 Hz, 1H), 4.45 (t,J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.17 (d, J = 9.1 Hz, 1H), 4.00-3.96 (m,2H), 3.69-3.59 (m, 4H), 3.45-3.34 (m, 2H), 3.14 (d, J = 8.7 Hz, 2H),2.76 (s, 3H), 2.63-2.59 (m, 2H), 2.48 (s, 3H), 2.31-2.27 (m, 2H),2.05-2.01 (m, 1H), 1.91-1.71 (m, 4H), 1.60 (s, 3H), 1.38 (d, J = 7.0 Hz,3H), 0.94 (s, 9H) H172

(2S,4R)-1-[(2S)-2- (2-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl]acet- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 693.35 (300 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.45(d, J = 10.0 Hz, 3H), 8.02 (d, J = 9.2 Hz, 1H), 7.45-7.38 (m, 4H), 7.22(t, J = 7.8 Hz, 1H), 6.98-6.76 (m, 4H), 4.92-7.88 (m, 1H), 4.59-4.33 (m,2H), 4.33-3.89 (m, 3H), 3.51-3.30 (m, 3H), 2.47 (s, 3H), 2.28-2.21 (m,2H), 2.10-1.69 (m, 4H), 1.41-1.35 (m, 3H), 0.91 (s, 9H) H173

(2S)-2-amino-N-[3- chloro-5-(5-[[(2S)- 1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pen- tyl)phenyl]pentane-diamide hydrochloride [(M − 1)]⁻ = 794.55 (300 MHz, DMSO-d₆) δ 11.05 (s,1H), 9.04 (s, 1H), 8.44 (s, 1H), 8.40 (d, J = 7.9 Hz, 2H), 7.81 (d, J =9.3 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.48-7.35 (m, 5H), 7.05 (d, J =1.9 Hz, 1H), 6.96 (s, 1H), 4.95-4.80 (m, 3H) 4.53 (d, J = 9.4 Hz, 1H),4.44 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.07 (s, 1H), 3.61 (s, 2H), 2.58(d, J = 7.4 Hz, 2H), 2.47 (s, 3H), 2.27 (t, J = 7.9 Hz, 3H), 2.18-2.01(m, 4H), 1.82-1.73 (m, 1H), 1.60-1.44 (m, 4H), 1.39 (d, J = 6.9 Hz, 3H),1.33-1.22 (m, 2H), 0.94 (s, 9H) H174

(2S)-2-amino-N-[3- (5-[[(2S)-1- [(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pen- tyl)-5-methylphenyl]pentane- diamide hydrochloride 776.35 (300 MHz, DMSO-d₆) δ9.78 (s, 1H), 9.00 (s, 1H), 8.52-8.43 (m, 3H), 7.79 (d, J = 9.2 Hz, 1H),7.49-7.38 (m, 4H), 7.29-7.18 (m, 3H), 7.00 (d, J = 7.8 Hz, 1H),6.79-6.72 (m, 2H), 5.10 (d, J = 3.5 Hz, 1H), 5.01-4.83 (m, 1H),4.63-4.36 (m, 2H), 4.30 (s, 1H), 4.06- 3.97 (m, 1H), 3.62 (d, J = 3.2Hz, 2H), 3.04-2.45 (m, 6H), 2.26 (s, 3H), 2.18-2.13 (m, 6H), 1.95-1.70(m, 2H), 1.62-1.51 (m, 4H), 1.32-1.24 (m, 4H), 0.95 (s, 9H) H175

(2S)-2-amino-N-[3- (5-[[(2S)-1- [(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]pen- tyl)-2-methylphenyl]pentane- diamide hydrochloride [(M − H)]⁻ = 774.45 (300MHz, DMSO-d₆) δ 10.18 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 8.49 (s, 3H),8.40 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.41 (q, J = 8.3 Hz,4H), 7.17 (dd, J = 5.5, 2.9 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.02 (d,J = 7.3 Hz, 1H), 6.77-6.64 (m, 2H), 4.95-4.90 (m, 1H), 4.51 (d, J = 9.2Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H), 4.13 (d, J = 5.8 Hz,1H), 3.70-3.56 (m, 3H), 2.57 (t, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.31 (t,J = 7.9 Hz, 2H), 2.15-1.95 (m, 4H), 1.86- 1.65 (m, 2H), 1.58-1.48 (m,5H), 1.37 (d, J = 7.0 Hz, 3H), 1.36-1.22 (m, 1H), 1.25- 1.14 (m, 1H),1.13-1.02 (m, 1H), 0.92 (s, 9H) H176

(2S,4R)-1-[(2S)-2- (3-[3-[(2S)-2- amino-4- carbamoylbu-toxy]phenyl]propan- amido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 707.35 (400 MHz, DMSO-d₆) δ 9.17 (s, 1H),8.49- 8.35 (m, 5H), 7.90 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H),7.40 (d, J = 8.1 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 6.91-6.76 (m, 3H),5.76 (s, 1H), 4.92 (t, J = 7.3 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43(t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.17 (dd, J = 10.4, 3.5 Hz, 1H), 4.04(dd, J = 10.4, 6.4 Hz, 1H), 3.60-3.55 (m, 3H), 2.78 (d, J = 7.7 Hz, 3H),2.60-2.55 (m, 1H), 2.48 (s, 3H), 2.30-2.24 (m, 1H), 2.08-1.73 (m, 5H),1.38-1.33 (m, 3H), 0.91 (s, 9H) H177

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-fluorophenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 739.30 (300 MHz, DMSO-d₆) δ 9.11 (s, 1H),8.44- 4.36 (m, 4H), 7.88 (d, J = 9.2 Hz, 1H), 7.44 (q, J = 8.1 Hz, 4H),7.12-7.04 (m, 2H), 6.95-6.85 (m, 2H), 4.92 (t, J = 7.2 Hz, 1H), 4.54 (d,J = 9.2 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.34-4.12 (m, 3H), 3.65-3.62(m, 2H), 3.53-3.49 (m, 2H), 2.61 (t, J = 7.1 Hz, 2H), 2.45 (s, 3H),2.27-2.22 (m, 3H), 2.09-1.89 (m, 2H), 1.87-1.74 (m, 5H), 1.39 (d, J =6.9 Hz, 3H), 0.96 (s, 9H) H178

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- amino-4- carbamoylbutoxy]-2-fluorophenyl]pentan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 753.35 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 7.83 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H),7.39 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.06-6.94 (m, 2H), 6.85-6.77 (m,2H), 6.76-6.67 (m, 2H), 5.12-5.10 (m, 1H), 4.92 (t, J = 7.1 Hz, 1H),4.56-4.48 (d, J = 7.3 Hz 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.29-4.27 (m,1H), 3.87-3.85 (m, 1H), 3.81-3.78 (m, 1H), 3.67-3.56 (m, 2H), 2.97-2.95(m, 1H), 2.60 (t, J = 6.9 Hz, 2H), 2.46 (s, 3H), 2.35-2.20 (m, 2H),2.17-2.14 (m, 2H), 2.03-1.99 (m, 1H), 1.86-1.70 (m, 2H), 1.57-1.44 (m,5H), 1.38 (d, J = 7.0 Hz, 3H), 0.94 (s, 9H) H179

(2S)-2-amino-N-[3- fluoro-5-(5-[[(2S)- 1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]- ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]pen- tyl)phenyl]pentane-diamide hydrochloride 780.25 (400 MHz, DMSO-d₆) δ 11.25 (s, 1H), 9.19(d, J = 5.6 Hz, 1H), 8.53 (d, J = 5.2 Hz, 3H), 8.43 (d, J = 7.8 Hz, 1H),7.80 (d, J = 9.2 Hz, 1H), 7.53-7.43 (m, 3H), 7.40 (d, J = 8.2 Hz, 2H),7.26 (s, 1H), 6.85-6.75 (m, 1H), 4.98-4.92 (m, 1H), 4.51 (d, J = 9.3 Hz,1H), 4.44 (q, J = 8.0, 7.3 Hz, 1H), 4.29 (d, J = 3.9 Hz, 1H), 4.10 (d, J= 5.8 Hz, 1H), 3.60 (d, J = 4.0 Hz, 2H), 2.55 (t, J = 7.7 Hz, 3H), 2.48(s, 3H), 2.34-2.19 (m, 3H), 2.19- 1.95 (m, 4H), 1.85-1.77 (m, 1H),1.64-1.42 (m, 5H), 1.38 (d, J = 6.9 Hz, 3H), 1.27 (q, J = 7.5 Hz, 2H),0.93 (s, 9H) H180

(2S,4R)-1-[(2S)-2- (6-[3-[(2-amino-4- carbamoylbu- tyl)amino]-2-fluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide trifluoroacetate 766.35 (400 MHz, DMSO-d₆) δ 9.01 (s, 1H),8.37 (d, J = 7.7 Hz, 1H), 7.86 (s, 2H), 7.79 (d, J = 9.2 Hz, 1H), 7.45(d, J = 7.8 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.97 (s, 1H), 6.90 (t, J= 7.7 Hz, 1H), 6.62 (t, J = 8.1 Hz, 1H), 6.50 (t, J = 7.0 Hz, 1H), 4.92(t, J = 7.2 Hz, 1H) 4.52 (d, J = 9.1 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H),4.29 (s, 1H), 3.56 (s, 2H), 3.32-3.18 (m, 3H), 2.48 (s, 3H), 2.29-2.25(m, 3H), 2.15-2.07 (m, 1H), 2.02 (d, J = 15.4 Hz, 2H), 1.84-1.80 (m,3H), 1.57-1.46 (m, 4H), 1.41-1.37 (m, 3H), 1.24-1.20 (m, 6H), 0.94 (s,9H) H181

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-fluoro-5-methylphenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 781.35 (300 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.38(d, J = 7.1 Hz, 3H), 7.77 (d, J = 9.2 Hz, 1H), 7.41 (q, J = 8.2 Hz, 5H),6.85 (d, J = 7.7 Hz, 2H), 6.67 (d, J = 5.9 Hz, 1H), 4.91 (t, J = 7.2 Hz,1H), 4.50 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.1 Hz, 1H), 4.30-4.25 (m,1H), 4.19 (dd, J = 10.5, 3.8 Hz, 1H), 4.14-4.05 (m, 1H), 3.62-3.58 (m,2H), 3.52-3.42 (m, 1H), 2.57-2.51 (m, 2H), 2.46 (s, 3H), 2.34- 2.26 (m,2H), 2.24 (s, 3H), 2.18-1.95 (m, 3H), 1.95-1.86 (m, 2H), 1.84-1.71 (m,1H), 1.58-1.44 (m, 4H), 1.41-1.34 (s, 3H), 1.31- 1.18 (m, 3H), 0.92(s,9H) H182

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2,5-difluorophenyl]hexan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 785.40 (300 MHz, CD3OD) δ 10.03 (s, 1H), 7.63-7.46 (m, 4H), 6.93-6.81 (m, 1H), 6.74-6.65 (m, 1H), 5.04 (q, J = 6.9 Hz,1H), 4.66-4.53 (m, 2H), 4.45 (br, 1H), 4.30 (dd, J = 10.5, 3.5 Hz, 1H),4.21-4.13 (m, 1H), 3.90 (d, J = 11.0 Hz, 1H), 3.76-3.69 (m, 5H), 2.72-2.65 (m, 1H), 2.63 (s, 3H), 2.52 (q, J = 7.0 Hz, 1H), 2.37-2.15 (m, 2H),2.15-2.03 (m, 2H), 2.01-1.87 (m, 1H), 1.69-1.57 (m, 4H), 1.53 (d, J =7.0 Hz, 3H), 1.47-1.27 (m, 2H), 1.05 (s, 9H) H183

(2S,4R)-1-[(2S)-2- (6-[2-[(1S)-1- amino-3- carbamoylpro- pyl]pyridin-4-yl]hexanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 720.30 (300 MHz, DMSO-d₆) δ 9.14 (s, 3H), 9.02(s, 1H), 8.87-8.85 (d, J = 6.0 Hz, 1H), 8.41-8.38 (d, J = 7.8 Hz, 1H),8.13 (s, 1H), 8.03 (s, 1H), 7.81-7.78 (d, J = 9.2 Hz, 1H), 7.45-7.27 (q,J = 8.3 Hz, 4H), 6.85 (s, 1H), 4.93-4.88 (t, J = 7.2 Hz, 1H), 4.53-4.38(m, 1H), 4.27 (s, 1H), 3.59 (s, 3H), 3.56 (s, 4H), 3.09-3.00 (m, 4H),2.45 (s, 2H), 2.33- 2.11 (m, 1H), 2.07 (s, 2H), 1.78-1.74 (m, 3H), 1.53(s, 2H), 1.38-1.28 (d, J = 7.0 Hz, 2H), 1.23-1.16 (m, 5H), 0.93 (s, 9H)H184

(2S)-2-amino-N-[3- (4-[[(2S)-1- [(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]bu- tyl)phenyl]pentane-diamide hydrochloride 748.40 (300 MHz, DMSO-d₆) δ 10.55 (s, 1H), 9.01(s, 1H), 8.39-8.30 (m, 5H), 7.82 (d, J = 9.1 Hz, 1H), 7.52-7.34 (m, 7H),7.30- 7.25 (m, 1H), 6.99-6.96 (m, 2H), 4.96-4.88 (m, 1H), 4.55-4.41 (m,2H), 4.31-4.28 (m, 1H), 4.04-3.96 (m, 1H), 2.61-2.57 (m, 2H), 2.47 (s,3H), 2.31-2.14 (m, 2H), 2.09-1.77 (m, 5H), 1.59-1.48 (m, 5H), 1.39 (d, J= 7.0 Hz, 3H), 1.27-1.25 (m, 1H), 0.95 (s, 9H) H185

4-[3-[(2S)-2-amino- 4- carbamoylbutoxy]- 2- fluorophenyl]butylN-[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl]car- bamoyl]pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamate hydrochloride 769.35 (400 MHz, DMSO-d₆) δ9.06 (s, 1H), 8.44 (s, 1H), 7.44 (d, J = 2.6 Hz, 3H), 7.39 (s, 1H), 7.32(s, 2H), 7.19 (s, 2H), 7.10-7.03 (m, 1H), 6.91 (s, 1H), 4.90 (q, J = 7.2Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.31-4.10 (m, 3H), 3.97 (d, J = 11.9Hz, 2H), 3.67-3.57 (m, 4H), 2.63 (d, J = 7.6 Hz, 2H), 2.47 (s, 3H),2.33-2.29 (m, 2H), 2.10-1.97 (m, 1H), 1.93 (s, 2H), 1.84-1.71 (m, 6H),1.62-1.58 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H), 0.94 (s, 9H) H186

(2S,4R)-1-[(2S)- 2-(4-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-chlorophenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[1-[4-(4-methyl- 1,3-thiazol-5- yl)phenyl]cyclo- propyl]pyrrolidine-2-carboxamide hydrochloride 767.20 (300 MHz, DMSO-d₆) δ 9.06 (s, 1H),8.88-8.83 (m, 1H), 8.39-8.33 (m, 2H), 8.02 (d, J = 9.2 Hz, 1H),7.51-7.46 (m, 1H), 7.38-7.31 (m, 3H), 7.30-7.19 (m, 2H), 7.10-7.02 (m,1H), 7.01-6.90 (m, 2H), 4.58 (d, J = 9.3 Hz, 1H), 4.45- 4.39 (m, 4H),3.68-3.65 (m, 1H), 3.63- 3.51 (m, 5H), 2.75-2.70 (m, 2H), 2.46 (s, 3H),2.37-2.20 (m, 4H), 2.04-1.94 (m, 3H), 1.85-1.76 (m, 2H), 1.29-1.23 (m,2H), 0.96 (s, 9H) H187

(2S)-2-amino-N- [2-chloro-3-(5- [[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)-1-[4-(4- methyl-1,3- thiazol-5- yl)phenyl]ethyl]car-bamoyl]pyrrolidin- 1-yl]-3,3- dimethyl-1- oxobutan-2- yl]carbamoyl]pen-tyl)phenyl]pentane- diamide hydrochloride 773.25 (300 MHz, DMSO-d₆) δ9.08 (s, 1H), 8.47-8.30 (m, 4H), 7.91 (d, J = 9.2 Hz, 1H), 7.48-7.38 (m,4H), 7.12-7.06 (m, 1H), 7.03 (s, 1H), 6.87 (dd, J = 9.2, 2.8 Hz, 1H),4.94-4.90 (m, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 7.9 Hz, 1H),4.35-4.24 (m, 2H), 4.19-3.77 (m, 2H), 3.60-3.57 (m, 2H), 2.71 (t, J =7.6 Hz, 2H), 2.48 (s, 3H), 2.34-2.30 (m, 3H), 2.19-1.98 (m, 4H),1.87-1.71 (m, 3H), 1.39 (d, J = 7.0 Hz, 3H), 1.26-1.24 (m, 1H), 0.96 (s,9H) H188

(2S,4R)-1-[(2S)- 2-(4-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2,5-difluorophenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4- methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide hydrochloride 757.30 (300 MHz, DMSO-d₆) δ 9.08 (s, 1H),8.40-8.36 (m, 3H), 7.91 (d, J = 9.2 Hz, 1H), 7.52-7.41 (m, 4H),7.42-4.38 (m, 2H), 7.07-7.01 (m, 2H), 6.77 (s, 1H), 5.13-5.10 (m, 1H),4.93 (t, J = 7.4 Hz, 1H), 4.54 (d, J = 9.1 Hz, 1H), 4.44 (t, J = 8.1 Hz,1H), 4.27 (d, J = 11.6 Hz, 2H), 4.20-4.18 (m, 1H), 3.64-3.60 (m, 3H),2.61-2.54 (m, 2H), 2.49 (s, 3H), 2.31-2.29 (m, 3H), 2.26-2.10 (m, 2H),1.98-1.95 (m, 2H), 1.79-1.72 (m, 3H), 1.39 (d, J = 7.0 Hz, 3H), 0.96 (s,9H) H189

(2S,4R)-1-[(2S)- 2-(4-[3-[(2S)-2- amino-4- carbamoylbutoxy]- 2-chloro-5-methylphenyl]butan- amido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4- methyl-1,3- thiazol-5- yl)phenyl]eth- yl]pyrrolidine-2-carboxamide 769.00 (400 MHz, DMSO-d₆) δ 9.09 (d, J = 1.6 Hz, 1H),8.46-8.32 (m, 4H), 7.89 (d, J = 9.3 Hz, 1H), 7.47-7.41 (m, 2H), 7.39 (d,J = 8.4 Hz, 2H), 6.94 (s, 1H), 6.89 (d, J = 1.9 Hz, 1H), 6.78 (d, J =1.8 Hz, 1H), 4.95-4.88 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.42 (t, J =8.0 Hz, 1H), 4.30- 4.26 (m, 1H), 4.24-4.20 (m, 1H), 4.13 (dd, J = 10.5,5.7 Hz, 1H), 3.62-3.61 (m, 2H), 3.57 (s, 3H), 2.66-2.61 (m, 2H), 2.47(s, 3H), 2.36-2.23 (m, 5H), 2.22-2.14 (m, 1H), 2.05-1.91 (m, 3H),1.83-1.73 (m, 3H), 1.38 (d, J = 7.0 Hz, 3H), 0.95 (s, 9H)

(9H-fluoren-9-yl)methyl((3S,6S)-6-(((2R,3S)-6-amino-2-((4-(3-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)propyl)benzyl)oxy)-6-oxohexan-3-yl)carbamoyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-yl)carbamate(Intermediate I)

To a solution of(3S,6S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indole-6-carboxylicacid (139 mg, 0.30 mmol) in DMA (7.00 mL) were added TEA (120 mg, 1.19mmol) and HATU (147 mg, 0.39 mmol) at 0° C. under nitrogen atmosphere.The resulting mixture was stirred for 10 min at room temperaturefollowed by the addition of(4S,5R)-4-amino-5-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)hexanamidehydrochloride (200 mg, 0.30 mmol). The resulting mixture was stirred for16 hours at room temperature under nitrogen atmosphere. Upon completion,the resulting mixture was purified by reversed phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 120 g; Eluent A: Water (plus 10 mmol/LAcOH); Eluent B: ACN;Gradient: 30%-50% B in 20 min; Flow rate: 50 mL/min; Detector: UV220/200 nm; desired fractions were collected at 46% B and concentratedunder reduced pressure to afford the title compound as a white solid(200 mg, 62%): ¹H NMR (400 MHz, DMSO-d₄) δ 11.08 (s, 1H), 7.90 (d, J=7.6Hz, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.75 (q, J=7.0 Hz, 3H), 7.43 (t, J=7.4Hz, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.31-7.26 (m, 1H), 7.20-7.08 (m, 4H),7.08-6.92 (m, 5H), 6.87 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 5.33 (dd,J=12.7, 5.4 Hz, 1H), 5.06 (d, J=10.6 Hz, 1H), 4.45 (s, 1H), 4.40 (s,2H), 4.27 (p, J=8.3, 7.3 Hz, 3H), 4.13 (s, 1H), 3.78 (s, 1H), 3.51 (s,3H), 3.48-3.38 (m, 4H), 3.32-3.33 (m, 9H), 3.05 (s, 2H), 2.85 (d, J=15.9Hz, 2H), 2.56-2.73 (m, 5H), 2.2.00-2.10 (m, 1H), 1.92-1.75 (m, 5H), 1.56(s, 1H), 1.07 (d, J=6.4 Hz, 3H); MS (ESI, m/z): [(M+1)]⁺=1088.30.

The following intermediates in Table 50 were synthesized according tothe above procedure to prepare Intermediate I.

TABLE 50 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H NMR I1 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(2-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]ethoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1088.6  (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.75(q, J = 8.0, 7.5 Hz, 3H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz,2H), 7.17 (d, J = 7.7 Hz, 3H), 7.12 (d, J = 7.8 Hz, 2H), 7.05 (d, J =7.7 Hz, 2H), 7.00-6.93 (m, 3H), 6.91-6.84 (m, 1H), 6.68 (s, 1H), 5.36(dd, J = 12.4, 5.4 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H), 4.39 (s, 2H),4.27 (s, 2H), 4.25 (s, 1H), 4.13 (s, 1H), 3.78 (s, 2H), 3.56 (m, 3H),3.52 (m, 3H), 3.44 (dt, J = 27.9, 6.2 Hz, 4H), 3.32 (s, 4H), 3.07 (d, J= 15.5 Hz, 1H), 2.96 (t, J = 7.8 Hz, 2H), 2.85 (d, J = 17.2 Hz, 2H),2.76-2.68 (m, 1H), 2.66-2.56 (m, 3H), 2.52 (s, 3H), 2.08 (s, 1H), 1.82 (m, 5H), 1.54 (s, 1H), 1.07 (d, J = 6.2 Hz, 3H). I2 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(2-[3-[3-methyl-1-(1- methyl-2,6- dioxopiperidin-3-yl)- 2-oxo-1,3-benzodiazol-4- yl]propoxy]ethoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate [(M + 23)]⁺ = 1102.8 (400 MHz,DMSO-d₆) δ 7.90 (d, J = 7.5 Hz, 2H), 7.83 (d, J = 9.3 Hz, 1H), 7.74 (q,J = 8.9, 8.0 Hz, 3H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz,2H), 7.26-7.08 (m, 4H), 7.04 (d, J = 7.4 Hz, 2H), 6.95 (d, J = 7.3 Hz,3H), 6.94-6.84 (m, 1H), 6.68 (s, 1H), 5.76 (d, J = 1.4 Hz, 2H),5.47-5.39 (m, 1H), 5.06 (d, J = 10.7 Hz, 1H), 4.41 (d, J = 12.5 Hz, 2H),4.26 (d, J = 7.7 Hz, 3H), 4.13 (s, 1H), 3.78 (s, 2H), 3.56 (s, 3H), 3.52(s, 4H), 3.49-3.36 (m, 5H), 3.32 (s, 1H), 3.03 (s, 3H), 2.96 (t, J = 7.8Hz, 2H), 2.89-2.77 (m, 1H), 2.77-2.66 (m, 1H), 2.61 (t, J = 7.8 Hz, 2H),2.50 (s, 2H), 2.08 (d, J = 1.5 Hz, 3H), 1.81 (m, 6 H), 1.56 (s, 1H),1.07 (d, J = 6.2 Hz, 3H). I3 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(3-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]propoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1102.6  (400 MHz, CDCl₃) δ 8.83(d, J = 35.6 Hz, 1H), 7.79 (d, J = 7.7 Hz, 2H), 7.64 (s, 2H), 7.42 (t, J= 7.5 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.16 (t, J = 7.7 Hz, 2H), 7.06(s, 3H), 6.93-6.84 (m, 2H), 6.72 (d, J = 7.9 Hz, 1H), 6.10 (d, J = 7.0Hz, 1H), 6.00 (s, 1H), 5.20 (d, J = 19.3 Hz, 2H), 4.58 (s, 1H), 4.39 (m,4H), 4.26 (s, 1H), 3.98 (s, 1H), 3.60 (s, 1H), 3.53 (t, J = 6.2 Hz, 3H),3.43 (s, 3H), 3.39 (s, 2H), 3.30 (s, 2H), 3.23 (s, 1H), 3.10 (d, J =17.8 Hz, 1H), 2.97-2.81 (m, 1H), 2.72 (dd, J = 19.5, 11.8 Hz, 5H), 2.32(s, 1H), 2.22 (s, 1H), 2.05 (s, 1H), 1.89 (d, J = 7.0 Hz, 5H), 1.65 (s,8H), 1.28 (s, 1H), 1.22 (s, 3H). I4 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(3-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]propoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1102.7  (400 MHz, CD₃OD) δ 7.81(d, J = 7.6 Hz, 2H), 7.70 (t, J = 8.4 Hz, 2H), 7.43-7.30 (m, 5H), 7.23(d, J = 7.7 Hz, 3H), 7.13 (d, J = 7.7 Hz, 3H), 7.09-7.00 (m, 5H),7.02-6.90 (m, 3H), 5.33 (d, J = 12.4 Hz, 1H), 5.11 (d, J = 10.8 Hz, 1H),4.47 (d, J = 8.3 Hz, 2H), 4.44-4.35 (m, 3H), 4.32 (d, J = 9.8 Hz, 1H),4.25 (s, 1H), 3.96 (s, 1H), 3.64 (s, 4H), 3.52 (dd, J = 12.3, 6.1 Hz,7H), 3.41 (d, J = 14.6 Hz, 1H), 3.13 (s, 2H), 3.08-3.00 (m, 3H), 2.79(d, J = 14.1 Hz, 3H), 2.68 (t, J = 7.7 Hz, 3H), 2.24 (s, 3H), 8, 1.87(s, 8H), 1.66 (s, 1H), 1.18 (d, J = 6.3 Hz, 3H). I5 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(4-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]butoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1116.6  (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.96-7.69 (m, 5H), 7.54 (s, 1H), 7.39 (dt, J = 34.1, 7.4Hz, 4H), 7.23- 6.93 (m, 10H), 6.87 (d, J = 8.1 Hz, 1H), 6.69 (s, 1H),5.34 (dd, J = 12.5, 5.4 Hz, 1H), 5.16-4.93 (m, 1H), 4.40 (s, 2H), 4.27(p, J = 5.9, 5.2 Hz, 2H), 4.12 (d, J = 6.8 Hz, 1H), 3.78 (s, 1H),3.45-3.34 (m, 9H), 3.12-2.98 (m, 2H), 2.87 (dd, J = 16.6, 9.6 Hz, 3H),2.64 (m, 9H), 2.25 (s, 1H), 2.16-1.94 (m, 5H), 1.80 (dp, J = 14.0, 6.7Hz, 5H), 1.56 (p, J = 3.2 Hz, 5H), 1.24 (s, 1H), 1.08 (d, J = 6.2 Hz,2H). I6 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(4-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]butoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1116.8  (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 9.0 Hz, 1H), 7.75(q, J = 7.3 Hz, 3H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.3 Hz, 2H),7.17 (d, J = 7.5 Hz, 3H), 7.11 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.7 Hz,2H), 6.99-6.93 (m, 2H), 6.86 (t, J = 4.5 Hz, 1H), 6.69 (s, 1H), 5.36(dd, J = 12.7, 5.4 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H), 4.40 (s, 2H),4.27 (dd, J = 12.5, 7.0 Hz, 2H), 4.13 (s, 1H), 3.78 (s, 1H), 3.56 (s,3H), 3.47-3.34 (m, 13 H), 3.30 (s, 1H), 2.95 (t, J = 7.9 Hz, 2H), 2.87(s, 1H), 2.67-2.56 (m, 3H), 2.53 (s, 3 H), 2.25 (s, 1H), 2.08 (s, 2H),1.80 (m , 5H), 1.57 (s, 5H), 1.08 (d, J = 6.2 Hz, 3H). I7 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[(6-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]hexyl)oxy] propyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1130.5  (400 MHz, CD₃OD) δ 7.81(d, J = 7.5 Hz, 1H), 7.70 (t, J = 8.3 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H),7.32 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.15-6.91 (m, 6H),5.30 (d, J = 7.5 Hz, 1H), 5.11 (d, J = 10.7 Hz, 1H), 4.48 (d, J = 8.7Hz, 1H), 4.41 (dd, J = 17.8, 8.9 Hz, 1H), 4.25 (s, 1H), 3.97 (s, 1H),3.56 (s, 1H), 3.44 (t, J = 6.5 Hz, 5H), 3.38 (s, 2H), 3.13 (s, 1H), 3.00(d, J = 17.6 Hz, 1H), 2.94-2.85 (m, 1H), 2.81 (s, 1H), 2.75 (t, J = 7.5Hz, 2H), 2.67 (t, J = 7.6 Hz, 1H), 2.24 (s, 2H), 2.16 (s, 2H), 1.99 (s,1H), 1.88 (dq, J = 14.6, 7.5, 7.0 Hz, 3H), 1.62 (d, J = 8.5 Hz, 4H),1.50 (d, J = 7.6 Hz, 2H), 1.31 (s, 1H), 1.18 (d, J = 6.3 Hz, 3H). I8 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[(5-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]pentyl)oxy] propyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1130.75 (400 MHz, CD₃OD) δ 7.81(d, J = 7.5 Hz, 2H), 7.72 (dt, J = 17.3, 8.1 Hz, 2H), 7.58 (s, 1H), 7.40(t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H),7.15-6.89 (m, 9H), 5.33 (dd, J = 12.0, 5.0 Hz, 1H), 5.10 (d, J = 10.8Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.47-4.35 (m, 2H), 4.34-4.23 (m,1H), 3.97 (d, J = 11.6 Hz, 1H), 3.64 (s, 3H), 3.55 (s, 2H), 3.52-3.40(m, 7H), 3.40 (d, J = 11.0 Hz, 1H), 3.32 (s, 3H), 3.12 (s, 2H),3.07-2.99 (m, 2H), 2.94-2.84 (m, 1H), 2.78 (d, J = 14.5 Hz, 2H), 2.67(t, J = 7.7 Hz, 2H), 2.24 (d, J = 7.5 Hz, 2H), 2.18- 2.03 (m, 3H), 1.88(s, 4H), 1.85 (d, J = 6.7 Hz, 1H), 1.62 (m, 6H), 1.50 (d, J = 6.8 Hz,1H), 1.18 (s, 3H). I9 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[(6-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]hexyl)oxy] propyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1144.7  (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.90 (d, J = 7.4 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.75(q, J = 8.1, 7.6 Hz, 3H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.3 Hz,2H), 7.17 (m, 3H), 7.14-6.94 (m, 7H), 6.86 (d, J = 7.9 Hz, 1H), 6.69 (s,1H), 5.34 (dd, J = 12.5, 5.5 Hz, 1H), 5.06 (d, J = 10.1 Hz, 1H), 4.40(s, 2H), 4.26 (d, J = 8.0 Hz, 3H), 4.13 (s, 1H), 3.78 (s, 2H), 3.44 (s,2H), 3.05 (s, 2H), 2.87 (s, 3H), 2.67-2.55 (m, 5H), 2.49 (m, 9H), 2.08(s, 1H), 2.02 (s, 5H), 1.79 (dt, J = 15.7, 7.5 Hz, 6H), 1.51 (m, 6H),1.33 (s, 1H), 1.24 (s, 1H), 1.08 (s, 3H). I10 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[(6-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]hexyl)oxy] propyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11- yl]carbamate 1144.8  (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 7.90 (dd, J = 7.7, 3.9 Hz, 2H), 7.84 (t, J = 7.3 Hz, 1H),7.75 (q, J = 8.1, 7.6 Hz, 3H), 7.43 (t, J = 4.5 Hz, 2H), 7.34 (dd, J =9.5, 5.6 Hz, 2H), 7.17 (d, J = 7.5 Hz, 3H), 7.10 (d, J = 7.8 Hz, 2H),7.05 (d, J = 7.7 Hz, 2H), 7.00-6.91 (m, 3H), 6.86 (dd, J = 5.6, 3.3 Hz,1H), 6.69 (s, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 5.06 (d, J = 10.6Hz, 1H), 4.40 (s, 2H), 4.28 (dd, J = 12.7, 7.1 Hz, 2H), 4.13 (s, 1H),3.78 (s, 1H), 3.56 (s, 3H), 3.33-3.46 ( m, 8H), 2.95 (t, J = 7.9 Hz,2H), 2.90- 2.81 (m, 2H), 2.77-2.58 (m, 2H), 2.58 (d, J = 8.2 Hz, 2H),2.51-2.52 (m, 3H), 2.12-1.94 (m, 5H), 1.69-1.85 (m, 6H), 1.52 (s, 5H),1.50 (d, J = 5.6 Hz, 1H), 1.32-1.36 (m, 4H), 1.08 (d, J = 6.2 Hz, 3H).I11 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[(6-[3-[3-methyl-1-(1- methyl-2,6- dioxopiperidin-3-yl)- 2-oxo-1,3-benzodiazol-5- yl]propoxy]hexyl)oxy] propyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1158.8  (400 MHz, DMSO-d₆) δ7.90 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.79-7.69 (m, 3H),7.43 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.18 (s, 1H), 7.16(s, 2H), 7.11 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.05- 6.97(m, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.85 (dd, J = 8.1, 1.6 Hz, 1H), 6.68(s, 1H), 5.40 (dd, J = 13.0, 5.3 Hz, 1H), 5.06 (d, J = 10.4 Hz, 1H),4.40 (s, 2H), 4.28 (dd, J = 12.5, 7.2 Hz, 3H), 4.13 (s, 1H), 3.78 (s,1H), 3.48-3.41 (m, 1H), 3.35-3.39 (m, 7H), 3.32 (s, 4H), 3.09 (s, 1H),3.04 (s, 3H), 3.02- 2.91 (m, 1H), 2.86 (d, J = 16.6 Hz, 1H), 2.77 (d, J= 17.1 Hz, 1H), 2.74- 2.65 (m, 1H), 2.67-2.53 (m, 4H), 2.08 (s, 3H),2.06-1.94 (m, 1H), 1.92 (s, 1H), 1.87-1.71 (m, 6H), 1.51 (s, 6H),1.39-1.29 (m, 4H), 1.08 (d, J = 6.2 Hz, 3H). I12 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[(7-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]heptyl)oxy] propyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1158.7  (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.75(q, J = 7.0 Hz, 3H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H),7.17 (d, J = 7.5 Hz, 3H), 7.14-6.92 (m, 7H), 6.90-6.82 (m, 1H), 6.69 (s,1H), 5.76 (s, 1H), 5.34 (dd, J = 12.6, 5.4 Hz, 1H), 5.06 (d, J = 10.5Hz, 1H), 4.40 (s, 2H), 4.27 (s, 2H), 4.13 (s, 1H), 3.78 (s, 1H), 3.45(d, J = 6.5 Hz, 1H), 3.35-3.34 (m, 5H), 3.06 (dt, J = 23.6, 12.4 Hz,2H), 2.86 (dd, J = 16.4, 9.8 Hz, 2H), 2.77- 2.54 (m, 7H), 2.11 (s, 0H),2.08-1.97 (m, 10H), 1.85-1.72 (m, 6H), 1.50 (s, 1H), 1.36 (s, 3H),1.35-1.25 (m, 6H), 1.24 (s, 1H), 1.08 (d, J = 6.2 Hz, 3H). I13 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[(8-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]octyl)oxy] propyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1172.5  (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 9.1 Hz, 1H), 7.75(q, J = 6.5, 5.8 Hz, 3H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.4 Hz,2H), 7.19-7.13 (m, 3H), 7.14-6.92 (m, 7H), 6.90-6.83 (m, 1H), 6.69 (s,1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 4.40(s, 2H), 4.27 (dd, J = 12.4, 7.0 Hz, 2H), 4.13 (s, 1H), 3.78 (s, 2H),3.48-3.29 (m, 7H), 3.13-2.98 (m, 2H), 2.97-2.81 (m, 2H), 2.76-2.61 (m,3H), 2.58 (t, J = 7.6 Hz, 3H), 2.19 (s, 1H), 2.08 (s, 1H), 2.07-2.04 (m,4H), 2.03- 1.95 (m, 1H), 1.89-1.70 (m, 6H), 1.60-1.45 (m, 5H), 1.40-1.35(m, 3H), 1.31-1.22 (m, 8H), 1.08 (d, J = 6.2 Hz, 3H). I14 

9H-fluoren-9-ylmethyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[(4-[3-[2-(2-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]ethoxy) ethoxy]propyl]phenyl) methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1132.7  (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.77- 7.67 (m, 3H), 7.43 (t, J= 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.25-7.13 (m, 3H), 7.10 (d, J =7.8 Hz, 2H), 7.07- 7.00 (m, 4H), 7.00-6.92 (m, 2H), 6.86 (dd, J = 8.0,1.6 Hz, 1H), 6.68 (s, 1H), 5.76 (s, 3H), 5.33 (dd, J = 12.7, 5.3 Hz,1H), 5.12-5.02 (m, 1H), 4.40 (s, 2H), 4.34-4.25 (m, 3H), 4.13 (s, 1H),3.76 (d, J = 18.5 Hz, 1H), 3.57-3.53 (m, 4H), 3.52-3.47 (m, 4H),3.45-3.35 (m, 5H), 3.18-2.97 (m, 2H), 2.93-2.80 (m, 3H), 2.72-2.63 (m,3H), 2.62-2.54 (m, 3H), 2.16-1.94 (m, 5H), 1.87-1.70 (m, 5H), 1.56 (s,1H), 1.07 (d, J = 6.3 Hz, 3H). I15 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[2-(2-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]ethoxy) ethoxy]propyl]phenyl) methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1132.8  (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 7.98-7.67 (m, 6H), 7.54 (s, 1H), 7.44-7.30 (m, 4H),7.19-6.91 (m, 9H), 6.86 (dd, J = 5.9, 3.1 Hz, 1H), 6.69 (s, 1H),5.82-5.65 (m, 5H), 5.36 (dd, J = 12.5, 5.4 Hz, 1H), 5.06 (d, J = 10.5Hz, 1H), 4.39 (s, 2H), 4.30-4.22 (m, 3H), 4.16-4.07 (m, 1H), 3.78 (s,1H), 3.58-3.35 (m, 15H), 3.13-3.03 (m, 1H), 2.95 (t, J = 7.8 Hz, 2H),2.85 (d, J = 17.8 Hz, 2H), 2.73-2.63 (m, 1H), 2.59 (t, J = 7.6 Hz, 2H),2.14-1.95 (m, 4H), 1.82-1.66 (m, 5H), 1.55 (d, J = 11.8 Hz, 1H), 1.07(d, J = 6.2 Hz, 3H). I16 

(9H-fluoren-9- yl)methyl N-[(2S,11S)- 2-[[(3S,4R)-1-carbamoyl-4-[(4-[16- [1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5-yl]- 4,7,10,13- tetraoxahexadecan-1-yl]phenyl)methoxy] pentan-3-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M/2 + 18)]⁺ = 606.4 (400 MHz, DMSO-d₆) δ 11.10(s, 1H), 7.94-7.82 (m, 3H), 7.81-7.72 (m, 3H), 7.43 (t, J = 7.5 Hz, 2H),7.35 (t, J = 7.4 Hz, 2H), 7.22-7.14 (m, 3H), 7.11 (d, J = 7.9 Hz, 2H),7.08-6.93 (m, 5H), 6.87 (dd, J = 8.1, 1.6 Hz, 1H), 6.71 (s, 1H), 5.34(dd, J = 12.7, 5.4 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.40 (s, 2H),4.28 (dd, J = 12.3, 6.8 Hz, 2H), 4.12 (dd, J = 8.5, 3.8 Hz, 1H), 3.79(s, 2H), 3.58-3.30 (m, 17H), 3.16-2.99 (m, 1H), 2.87 (t, J = 13.9 Hz,2H), 2.77-2.54 (m, 6H), 2.54-2.51 (m, 7H), 2.09 (s, 1H), 2.07-1.96 (m,1H), 1.85-1.69 (m, 6H), 1.56 (s, 1H), 1.08 (d, J = 6.2 Hz, 3H). I17 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[[(2S)-1-(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]phenyl) methoxy]pentan-3- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1143.8  (400 MHz, DMSO-d₆) δ 8.97 (d, J = 11.4 Hz,1H), 8.58 (d, J = 7.5 Hz, 1H), 7.92-7.83 (m, 4H), 7.79 (t, J = 8.3 Hz,1H), 7.75-7.71 (m, 4H), 7.45-7.36 (m, 5H), 7.34-7.30 (m, 4H), 7.17 (s,1H), 7.05 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 14.2 Hz, 1H), 6.96 (s, 1H),6.69 (s, 1H), 5.16 (d, J = 3.6 Hz, 1H), 5.06 (s, 1H), 4.78 (t, J = 8.5Hz, 1H), 4.54- 4.43 (m, 3H), 4.39 (s, 1H), 4.28 (s, 1H), 4.32-4.20 (m,4H), 3.82 (s, 1H), 3.73 (d, J = 8.1 Hz, 2H), 3.32-3.26 (m, 3H), 3.18 (d,J = 5.2 Hz, 1H), 3.06 (s, 2H), 2.88-2.79 (m, 1H), 2.50-2.40 (m, 4H),2.13-2.01 (m, 6H), 1.78 (s, 2H), 1.56 (s, 1H), 1.04 (d, J = 9.0 Hz, 9H).I18 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1157.8  (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.10 (d, J = 9.3 Hz,1H), 7.90 (d, J = 7.5 Hz, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.78-7.71 (m,3H), 7.54 (s, 1H), 7.47-7.30 (m, 8H), 7.25-7.14 (m, 5H), 7.06 (d, J =7.9 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 5.12 (d, J = 3.6 Hz, 1H),5.10-5.02 (m, 1H), 4.53 (d, J = 9.4 Hz, 1H), 4.49-4.38 (m, 4H), 4.35 (s,1H), 4.32- 4.18 (m, 4H), 4.12 (d, J = 7.1 Hz, 1H), 3.78 (s, 1H),3.71-3.59 (m, 3H), 3.45- 3.37 (m, 1H), 3.32 (s, 3H), 3.08 (dd, J = 16.6,7.4 Hz, 1H), 2.47-2.43 (m, 3H), 2.08-2.07 (m, 3H), 2.08 (s, 3H), 2.04(s, 2H), 2.04 (d, J = 16.8 Hz, 2H), 1.96-1.85 (m, 1H), 1.07 (d, J = 6.2Hz, 3H), 0.92 (s, 9H). I19 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(2-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]ethyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1171.8  (400 MHz,CDCl₃) δ 8.71 (s, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.4 Hz,2H), 7.53 (s, 1H), 7.46-7.39 (m, 2H), 7.38-7.30 (m, 5H), 7.26 (s, 1H),7.13 (d, J = 7.4 Hz, 1H), 7.12- 7.02 (m, 3H), 6.84 (d, J = 10.1 Hz, 1H),6.22-6.07 (m, 1H), 5.92 (d, J = 46.8 Hz, 1H), 5.21-5.05 (m, 1H), 4.97(s, 1H), 4.68 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 11.8 Hz, 1H), 4.52 (d, J= 8.0 Hz, 3H), 4.43 (d, J = 7.6 Hz, 2H), 4.35 (d, J = 19.6 Hz, 2H),4.28-4.19 (m, 1H), 4.06-3.82 (m, 2H), 3.60 (dd, J = 10.7, 4.0 Hz, 2H),3.44-3.31 (m, 2H), 3.21 (d, J = 8.3 Hz, 1H), 3.10 (d, J = 17.3 Hz, 1H),2.96 (t, J = 7.4 Hz, 1H), 2.88 (s, 1H), 2.62 (s, 1H), 2.60-2.50 (m, 4H),2.43 (s, 1H), 2.29 (s, 1H), 2.12 (d, J = 12.3 Hz, 1H), 2.03 (s, 3H),1.88-1.78 (m, 3H), 1.21 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H). I20 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1215.8  (400 MHz, DMSO-d₆) δ8.97 (s, 1H), 8.61 (t, J = 6.2 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.84(d, J = 9.1 Hz, 1H), 7.80-7.69 (m, 3H), 7.43-7.35 (m, 9H), 7.18-7.11 (m,5H), 7.05 (d, J = 7.6 Hz, 2H), 6.97 (d, J = 7.4 Hz, 1H), 6.69 (s, 1H),5.81-5.72 (m, 3H), 5.16 (d, J = 3.5 Hz, 1H), 5.06 (d, J = 10.7 Hz, 1H),4.57 (d, J = 9.5 Hz, 1H), 4.46 (t, J = 8.3 Hz, 1H), 4.38 (s, 2H),4.30-4.23 (m, 3H), 4.13 (s, 1H), 3.94 (s, 2H), 3.78 (s, 1H), 3.70-3.59(m, 2H), 3.58 (s, 1H), 3.52-3.44 (m, 4H), 3.06 (s, 2H), 2.85 (d, J =16.8 Hz, 1H), 2.64 (t, J = 7.8 Hz, 2H), 2.42 (s, 2H), 2.15- 2.04 (m,5H), 1.95-1.71 (m, 4H), 1.07 (d, J = 6.2 Hz, 3H), 0.95 (s, 9H). I21 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-([[(2S)-1-[(2S,4S)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1215.8  (400 MHz, DMSO-d₆) δ8.97 (s, 1H), 8.67 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.83(d, J = 9.2 Hz, 1H), 7.77-7.70 (m, 3H), 7.48-7.35 (m, 7H), 7.16-7.10 (m,6H), 7.07-7.01 (m, 3H), 7.00-6.93 (m, 1H), 5.76 (s, 1H), 5.45 (d, J =7.3 Hz, 1H), 5.06 (d, J = 10.4 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H),4.47-4.35 (m, 5H), 4.35-4.24 (m, 5H), 4.12 (d, J = 10.6 Hz, 1H), 3.93(d, J = 2.2 Hz, 2H), 3.63-3.50 (m, 7H), 3.46 (dt, J = 11.9, 6.2 Hz, 3H),2.86 (d, J = 16.6 Hz, 1H), 2.64 (t, J = 7.7 Hz, 2H), 2.43 (s, 3H),2.12-2.07 (m, 5H), 1.08 (d, J = 6.1 Hz, 3H), 0.97 (s, 9H). I22 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[4-([[(2,S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) butyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1229.2  (400 MHz, DMSO-d₆) δ8.98 (d, J = 2.4 Hz, 1H), 8.60 (s, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.83(d, J = 9.4 Hz, 1H), 7.80-7.66 (m, 3H), 7.47-7.29 (m, 9H), 7.19-7.09 (m,5H), 7.05 (d, J = 7.8 Hz, 2H), 6.97 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H),5.82-5.71 (m, 4H), 5.15 (s, 1H), 5.06 (d, J = 10.6 Hz, 1H), 4.57 (d, J =9.6 Hz, 1H), 4.47 (d, J = 8.3 Hz, 1H), 4.34-4.30 (m, 3H), 4.30-4.22 (m,3H), 4.13 (s, 1H), 3.92 (s, 1H), 3.78 (s, 1H), 3.70-3.58 (m, 2H), 3.50(s, 4H), 3.06 (s, 1H), 2.86 (d, J = 16.8 Hz, 1H), 2.58 (d, J = 6.8 Hz,2H), 2.47-2.42 (m, 3H), 2.15-2.00 (m, 4H), 1.90 (d, J = 10.5 Hz, 1H),1.79 (s, 1H), 1.74-1.57 (m, 5H), 1.07 (d, J = 6.2 Hz, 3H), 0.95 (d, J =1.9 Hz, 9H). I23 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[4-([[(2,S)-1-[(2S,4S)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) butyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1229.7  (400 MHz, DMSO-d₆) δ8.98 (s, 1H), 8.66 (d, J = 5.9 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.83(d, J = 9.3 Hz, 1H), 7.80-7.70 (m, 3H), 7.47-7.30 (m, 7H), 7.20-7.11 (m,3H), 7.10 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.00- 6.92 (m,1H), 6.68 (s, 1H), 5.44 (d, J = 7.3 Hz, 1H), 5.06 (d, J = 10.4 Hz, 1H),4.52 (d, J = 9.3 Hz, 1H), 4.47- 4.34 (m, 4H), 4.34-4.20 (m, 5H), 4.13(s, 1H), 3.93-3.85 (m, 2H), 3.78 (s, 1H), 3.51-3.39 (m, 4H), 3.05 (s,2H), 2.86 (d, J = 16.9 Hz, 1H), 2.58 (t, J = 7.3 Hz, 2H), 2.50-2.49 (m,5H), 2.43 (s, 3H), 2.08 (s, 1H), 1.75 (s, 1H), 1.62 (d, J = 8.3 Hz, 2H),1.58-1.52 (m, 4H), 1.07 (d, J = 6.2 Hz, 3H), 0.95 (s, 9H). I24 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1200.0  (400 MHz,CD₃OD) δ 8.88 (s, 1H), 8.63 (t, J = 6.1 Hz, 1H), 7.81 (d, J = 7.8 Hz,2H), 7.69 (t, J = 8.4 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.43-7.38 (m,4H), 7.32 (t, J = 7.5 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.12 (d, J =7.9 Hz, 2H), 7.10-7.00 (m, 3H), 5.12 (d, J = 10.6 Hz, 1H), 4.65 (d, J =8.9 Hz, 1H), 4.57 (t, J = 8.3 Hz, 1H), 4.49 (s, 1H), 4.46 (d, J = 11.4Hz, 1H), 4.38 (d, J = 5.9 Hz, 1H), 4.36-4.29 (m, 2H), 4.25 (t, J = 6.9Hz, 1H), 4.02-3.88 (m, 2 H), 3.81 (dd, J = 10.9, 3.9 Hz, 1H), 3.63 (q, J= 7.1 Hz, 1H), 3.58-3.53 (m, 1H), 3.46 (dd, J = 16.5, 11.0 Hz, 1H), 3.37(s, 4H), 3.14 (s, 2H), 3.01 (d, J = 16.9 Hz, 1H), 2.62 (s, 2H), 2.48 (s,3H), 2.31-2.15 (m, 6H), 2.09 (ddd, J = 13.3, 9.1, 4.6 Hz, 1H), 2.01 (s,1H), 1.70-1.61 (m, 4H), 1.20-1.17 (m, 3H), 1.04 (s, 9H). I25 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4S)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1199.1  (400 MHz,DMSO-d₆) δ 8.99 (d, J = 2.5 Hz, 1H), 8.62 (t, J = 6.1 Hz, 1H), 7.93-7.86(m, 2H), 7.88-7.80 (m, 1H), 7.79-7.63 (m, 3H), 7.47-7.24 (m, 9H), 7.17(d, J = 7.7 Hz, 3H), 7.13-7.02 (m, 4H), 6.97 (t, J = 7.4 Hz, 1H), 6.68(s, 1H), 5.43 (dd, J = 6.9, 1.7 Hz, 1H), 5.10-5.03 (m, 1H), 4.51-4.32(m, 4H), 4.29-4.20 (m, 4H), 3.94 (dd, J = 10.2, 5.7 Hz, 1H), 3.79 (s,1H), 3.44 (dd, J = 9.7, 5.3 Hz, 3H), 2.86 (d, J = 16.6 Hz, 1H), 2.54 (d,J = 7.5 Hz, 2H), 2.44 (d, J = 3.5 Hz, 3H), 2.31 (s, 2H), 2.50- 2.49 (m,4H), 2.09 (s, 4H), 2.08 (s, 2H), 1.75 (dt, J = 12.3, 5.9 Hz, 1H),1.58-1.47 (m, 5H), 1.08 (d, J = 6.2 Hz, 3H), 0.96-0.89 (m, 9H). I26 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[2-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) ethoxy]propyl]phenyl)methoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1259.7  (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.60(t, J = 6.1 Hz, 1H), 7.95-7.81 (m, 3H), 7.80-7.71 (m, 3H), 7.47-7.38 (m,6H), 7.37-7.30 (m, 3H), 7.21-7.13 (m, 3H), 7.12-7.00 (m, 4H), 6.97 (d, J= 7.4 Hz, 1H), 6.70 (s, 1H), 5.22- 5.03 (m, 2H), 4.58 (d, J = 9.5 Hz,1H), 4.49-4.33 (m, 5H), 4.14 (d, J = 9.5 Hz, 1H), 3.99 (s, 2H), 3.78 (s,1H), 3.71- 3.37 (m, 11H), 3.18-2.99 (m, 2H), 2.85 (d, J = 16.3 Hz, 1H),2.58 (t, J = 7.8 Hz, 2H), 2.43 (s, 3H), 2.16-1.97 (m, 5H), 1.97-1.86 (m,3H), 1.79 (t, J = 7.5 Hz, 3H), 1.55 (s, 1H), 1.06 (t, J = 6.9 Hz, 3H),0.96 (s, 9H). I27 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[2-[2-([[(2S)-1-[(2S,4R)- 4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) ethoxy]ethoxy]propyl)phenyl]methoxy]pentan- 3-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M/2 + 1)]⁺ = 652.8 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.60 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.84 (d, J =9.3 Hz, 1H), 7.81-7.71 (m, 3H), 7.46-7.38 (m, 6H), 7.35 (q, J = 7.1 Hz,3H), 7.19-7.12 (m, 3H), 7.12-7.03 (m, 4H), 6.97 (d, J = 7.4 Hz, 1H),6.69 (s, 1H), 5.15 (d, J = 3.5 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 4.57(d, J = 9.5 Hz, 1H), 4.45 (t, J = 8.2 Hz, 1H), 4.42-4.34 (m, 5H),4.31-4.21 (m, 4H), 4.13 (d, J = 6.5 Hz, 1H), 3.98 (s, 2H), 3.78 (s, 1H),3.68 (dd, J = 10.7, 3.8 Hz, 1H), 3.65-3.51 (m, 7H), 3.49 (t, J = 4.8 Hz,2H), 3.44 (t, J = 6.7 Hz, 2H), 3.39 (d, J = 5.9 Hz, 1H), 3.36 (d, J =6.3 Hz, 1H), 3.05 (t, J = 15.6 Hz, 2H), 2.91-2.79 (m, 2H), 2.62-2.53 (m,3H), 2.44 (s, 3 H), 2.04 (q, J = 8.3, 6.8 Hz, 2H), 1.83- 1.70 (m, 3H),1.55 (d, J = 12.1 Hz, 1H), 1.08 (d, J = 6.2 Hz, 3H), 0.95 (s, 9H). I28 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(1-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]- 2,5,8,11- tetraoxatetradecan-14-yl)phenyl]methoxy] pentan-3-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M + 23)]⁺ = 1370.0  (400 MHz, DMSO-d₆) δ 8.98(d, J = 3.2 Hz, 1H), 8.60 (s, 1H), 7.90 (d, J = 7.4 Hz, 2H), 7.84 (d, J= 8.8 Hz, 1H), 7.82-7.70 (m, 3H), 7.46-7.36 (m, 7H), 7.34 (t, J = 7.4Hz, 2H), 7.22-7.15 (m, 3H), 7.14-7.02 (m, 4H), 6.97 (d, J = 7.7 Hz, 1H),6.69 (s, 1H), 5.15 (d, J = 3.5 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H), 4.57(d, J = 9.7 Hz, 1H), 4.49- 4.35 (m, 5H), 4.30-4.24 (m, 3H), 4.11- 4.05(m, 3H), 3.97 (s, 2H), 3.78 (s, 1H), 3.68-3.44 (m, 12H), 3.40-3.28 (m,10H), 2.62-2.55 (m, 3H), 2.50-2.42 (m, 3H), 2.11-2.04 (m, 5H), 1.91 (s,1H), 1.08 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 2.7 Hz, 9H). I29 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1185.5  (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.90-7.73 (m, 5H),7.74-7.68 (m, 4H), 7.46-7.30 (m, 7H), 7.22-7.14 (m, 3H), 7.13-7.02 (m,4H), 7.01-6.93 (m, 1H), 6.70 (s, 1H), 5.76 (s, 2H), 5.12 (d, J = 3.6 Hz,1H), 5.06 (d, J = 10.5 Hz, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.49-4.38 (m,5H), 4.36 (s, 1H), 4.32-4.17 (m, 4H), 3.78 (s, 2H), 3.67 (s, 2H),3.48-3.40 (m, 2H), 3.12-3.04 (m, 3H), 2.95 (s, 1H), 2.83 (d, J = 32.1Hz, 2H), 2.60-2.51 (m, 3H), 2.09 (s, 4H), 2.02 (d, J = 8.7 Hz, 3H), 1.95(d, J = 14.0 Hz, 1H), 1.94- 1.85 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H), 0.95(s, 9H). I30 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[2-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) ethyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate [(M/2 + 1)]⁺ = 601.7 (400 MHz,DMSO-d₆) δ 8.97 (s, 1H), 8.61 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.6 Hz,2H), 7.84 (d, J = 9.2 Hz, 1H), 7.80-7.70 (m, 3H), 7.47-7.38 (m, 5H),7.37 (dd, J = 9.0, 2.7 Hz, 2H), 7.33 (d, J = 7.3 Hz, 1H), 7.22-7.15 (m,3H), 7.05 (d, J = 7.8 Hz, 2H), 7.01-6.92 (m, 1H), 6.70 (s, 1H), 5.16 (d,J = 3.5 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H), 4.55 (d, J = 9.6 Hz, 1H),4.44 (dt, J = 16.2, 8.7 Hz, 2H), 4.44-4.32 (m, 3H), 4.30-4.24 (m, 4H),3.98-3.88 (m, 2H), 3.78 (s, 1H), 3.75-3.63 (m, 1H), 3.61 (d, J = 10.6Hz, 1H), 3.43 (q, J = 11.8, 10.4 Hz, 2H), 3.33 (s, 1H), 3.14-3.03 (m,1H), 3.06 (s, 1H), 2.89-2.81 (m, 3H), 2.43 (s, 3H), 2.12-2.04 (m, 3H),1.96-1.85 (m, 1H), 1.78 (s, 1H), 1.55 (d, J = 12.3 Hz, 1H), 1.06 (d, J =6.2 Hz, 3H), 0.93 (s, 9H). I31 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[2-[2-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) ethoxy]ethyl]phenyl) methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1245.9  (400 MHz, DMSO-d₆) δ8.97 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.84(d, J = 9.2 Hz, 1H), 7.80-7.69 (m, 3H), 7.47-7.31 (m, 8H), 7.24-7.11 (m,4H), 7.06 (d, J = 7.6 Hz, 2H), 7.01-6.93 (m, 1H), 6.68 (s, 1H), 5.15 (d,J = 3.5 Hz, 1H), 5.07 (d, J = 10.5 Hz, 1H), 4.59 (d, J = 9.6 Hz, 1H),4.47 (t, J = 8.1 Hz, 1H), 4.48-4.37 (m, 4H), 4.32-4.24 (m, 4H), 4.14 (s,1H), 3.98 (s, 2H), 3.79 (s, 2H), 3.69 (dd, J = 10.7, 4.0 Hz, 1H),3.66-3.54 (m, 7H), 3.14-2.99 (m, 1H), 2.88 (s, 1H), 2.82 (t, J = 7.2 Hz,2H), 2.43 (s, 3H), 2.15-2.04 (m, 6H), 1.98-1.87 (m, 1H), 1.79 (s, 1H),1.57 (s, 1H), 1.08 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H). I32 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(2-[2-[2-([[(2S)-1-[(2S,4R)- 4-hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methoxy) ethoxy]ethoxy]ethyl)phenyl]methoxy]pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1289.8  (400 MHz, CD₃OD) δ 8.86 (s, 1H), 7.82 (d,J = 7.7 Hz, 2H), 7.70 (t, J = 8.3 Hz, 2H), 7.59 (s, 1H), 7.49-7.37 (m,6H), 7.33 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.6 Hz, 2H), 7.16 (d, J =7.9 Hz, 2H), 7.10-6.99 (m, 3H), 5.13 (d, J = 10.7 Hz, 1H), 4.71 (s, 1H),4.63-4.46 (m, 4H), 4.45-4.22 (m, 6H), 4.10-3.97 (m, 2H), 3.89 (d, J =11.1 Hz, 1H), 3.85-3.78 (m, 1H), 3.70-3.61 (m, 11 H), 3.58 (d, J = 17.6Hz, 1H), 3.44 (d, J = 11.2 Hz, 1H), 3.14 (s, 1H), 3.01 (d, J = 16.6 Hz,1H), 2.83 (t, J = 6.9 Hz, 2H), 2.47 (s, 3H), 2.30-2.20 (m, 5H), 2.07 (d,J = 16.1 Hz, 1H), 2.00 (s, 2H), 1.67 (s, 1H), 1.19 (d, J = 6.5 Hz, 3H),1.05 (s, 9H). I33 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(1-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]- 2,5,8,11- tetraoxatridecan-13-yl)phenyl]methoxy] pentan-3-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1333.9  (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.60(t, J = 6.0 Hz, 1H), 7.90-7.82 (m, 3H), 7.80-7.73 (m, 3H), 7.47-7.36 (m,6H), 7.35 (q, J = 7.2 Hz, 3H), 7.20-7.12 (m, 5H), 7.05 (d, J = 7.7 Hz,2H), 7.00-6.93 (m, 1H), 6.69 (s, 1H), 5.15 (s, 1H), 5.10-5.02 (m, 1H),4.57 (d, J = 9.6 Hz, 1H), 4.48-4.34 (m, 5H), 4.32-4.24 (m, 4H), 4.13 (q,J = 7.6, 6.1 Hz, 1H), 3.97 (s, 2H), 3.78 (s, 1H), 3.68 (dd, J = 10.7,3.9 Hz, 1H), 3.65- 3.47 (m, 16H), 3.47-3.37 (m, 3H), 3.07 (q, J = 18.5,13.8 Hz, 2H), 2.90- 2.82 (m, 1H), 2.78 (q, J = 7.0, 5.7 Hz, 2H), 2.44(s, 3H), 2.07-2.00 (m, 2H), 1.96-1.91 (m, 1H), 1.78 (s, 1H), 1.56 (d, J= 12.0 Hz, 1H), 1.08 (d, J = 6.2 Hz, 3H), 0.95 (s, 9H). I44 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1213.2  (400 MHz,CDCl₃) δ 8.71 (s, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.5 Hz,2H), 7.41 (q, J = 7.4 Hz, 2H), 7.37-7.30 (m, 5H), 7.26 (d, J = 7.7 Hz,2H), 7.13 (d, J = 7.8 Hz, 2H), 7.11-7.01 (m, 3H), 6.83 (d, J = 9.5 Hz,1H), 6.24 (d, J = 8.6 Hz, 1H), 6.11- 5.89 (m, 2H), 5.25-5.00 (m, 2H),4.69 (t, J = 7.9 Hz, 1H), 4.66-4.46 (m, 2H), 4.46-4.19 (m, 6H), 4.10 (d,J = 11.3 Hz, 1H), 3.69-3.51 (m, 2H), 3.33 (d, J = 11.4 Hz, 1H), 3.16 (d,J = 46.2 Hz, 1H), 2.57 (t, J = 7.7 Hz, 2H), 2.53 (s, 3H), 2.28 (d, J =13.7 Hz, 1H), 2.24- 1.96 (m, 9H), 1.77 (s, 2H), 1.67-1.53 (m, 4H),1.40-1.15 (m, 5H), 0.93 (s, 9H). I45 

9H-fluoren-9-ylmethyl N-(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(6-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]hexyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate [(M + 2)/2]⁺ =614.6 (400 MHz, CD₃OD) δ 8.88 (s, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.70(t, J = 8.3 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.45-7.37 (m, 4H), 7.33(t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.15- 6.99 (m, 6H), 5.13(d, J = 10.6 Hz, 1H), 4.67-4.40 (m, 6H), 4.30 (s, 1H), 3.92 (d, J = 11.0Hz, 1H), 3.81 (dd, J = 10.9, 3.9 Hz, 1H), 3.63-3.40 (m, 2H), 3.07 (d, J= 61.1 Hz, 3H), 2.60 (t, J = 7.6 Hz, 2H), 2.48 (s, 3H), 2.25 (dq, J =14.6, 8.1, 7.2 Hz, 5H), 2.14- 1.95 (m, 2H), 1.62 (s, 7H), 1.34 (d, J =18.9 Hz, 6H), 1.19 (d, J = 6.4 Hz, 4H), 1.05 (s, 9H). I46 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]methoxy]propyl) phenyl]methoxy]pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1016.5  (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.90(d, J = 7.4 Hz, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.77-7.69 (m, 3H), 7.42(t, J = 7.4 Hz, 2H), 7.35 (d, J = 7.4 Hz, 2H), 7.17-7.13 (m, 4H), 7.09(t, J = 9.3 Hz, 2H), 7.07-6.99 (m, 3H), 7.02-6.92 (m, 1H), 6.68 (s, 1H),5.43- 5.35 (m, 1H), 5.05 (d, J = 10.4 Hz, 1H), 4.69 (s, 2H), 4.39 (s,2H), 4.27- 4.26 (m, 3H), 4.12 (s, 1H), 3.77 (s, 2H), 3.59 (d, J = 2.8Hz, 3H), 3.47 (t, J = 6.5 Hz, 2H), 3.42 (s, 3H), 3.05 (s, 1H), 2.86 (t,J = 14.7 Hz, 2H), 2.72 (d, J = 13.3 Hz, 1H), 2.67-2.55 (m, 2H), 2.07 (d,J = 3.2 Hz, 1H), 2.05 (s, 2H), 2.00 (s, 1H), 1.82 (s, 2H), 1.54 (s, 2H),1.07 (d, J = 6.2 Hz, 3H). I47 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(5-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]propoxy]pentyl) phenyl]methoxy]pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1072.9  (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.90(d, J = 7.5 Hz, 2H), 7.84 (t, J = 8.3 Hz, 1H), 7.79-7.71 (m, 3H), 7.43(t, J = 7.5 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.20-6.94 (m, 10H),6.89-6.83 (m, 1H), 6.68 (s, 1H), 5.34 (dd, J = 12.6, 5.3 Hz, 1H), 5.06(d, J = 10.6 Hz, 1H), 4.40 (s, 2H), 4.28- 4.24 (m, 3H), 4.13 (s, 1H),3.78 (s, 1H), 3.43 (s, 2H), 3.38-3.32 (m, 6H), 3.09 (s, 1H), 3.07-2.98(m, 1H), 2.88 (s, 1H), 2.75-2.52 (m, 4H), 2.08 (s, 2H), 1.85-1.78 (m,4H), 1.55 (dd, J = 14.8, 7.5 Hz, 6H), 1.41-1.31 (m, 2H), 1.07 (d, J =6.2 Hz, 3H). I48 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(5-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]pentyl) phenyl]methoxy]pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1072.8  (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.90(d, J = 7.7 Hz, 2H), 7.84 (t, J = 7.6 Hz, 1H), 7.79-7.71 (m, 3H), 7.43(t, J = 7.4 Hz, 2H), 7.34 (dd, J = 9.7, 5.2 Hz, 2H), 7.19-7.15 (m, 3H),7.11 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 6.98-6.95 (m, 3H),6.85 (dd, J = 5.8, 3.2 Hz, 1H), 6.69 (s, 1H), 5.37 (dd, J = 12.5, 5.4Hz, 1H), 5.06 (d, J = 10.4 Hz, 1H), 4.39 (s, 2H), 4.27-4.26 (m, 3H),4.13 (s, 1H), 3.78 (s, 1H), 3.45-3.28 (m, 6H), 3.32 (s, 2H), 3.06 (q, J= 17.1, 13.3 Hz, 1H), 2.94 (t, J = 7.8 Hz, 2H), 2.88 (s, 2H), 2.75-2.62(m, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.08 (s, 2H), 1.85-1.79 (m, 4H), 1.56(dt, J = 14.8, 7.7 Hz, 6H), 1.34 (d, J = 7.7 Hz, 2H), 1.07 (d, J = 6.2Hz, 3H). I49 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(2-[3-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]propoxy]ethyl)phenyl] methoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1030.3  (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.90(d, J = 7.5 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.75 (q, J = 7.8, 7.4 Hz,3H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.19-7.15 (m,5H), 7.05 (d, J = 7.7 Hz, 2H), 7.00-6.90 (m, 3H), 6.81 (dd, J = 6.4, 2.4Hz, 1H), 6.69 (s, 1H), 5.36 (dd, J = 12.5, 5.4 Hz, 1H), 5.06 (d, J =11.0 Hz, 1H), 4.41 (s, 2H), 4.32-4.26 (m, 3H), 4.13 (s, 1H), 3.78 (s,1H), 3.58 (q, J = 10.4, 8.6 Hz, 2H), 3.46 (d, J = 5.6 Hz, 1H), 3.13-3.03(m, 2H), 3.01-2.80 (m, 6H), 2.81 (t, J = 6.9 Hz, 2H), 2.76-2.66 (m, 1H),2.64 (s, 1H), 2.60 (s, 1H), 2.08 (s, 4H), 1.82-1.80 (m, 4H), 1.56 (s,2H), 1.07 (d, J = 6.2 Hz, 3H). I50 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[4-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]butyl]phenyl)methoxy] pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1000.7  (400 MHz, CDCl₃) δ 8.53 (s, 1H), 7.78 (d,J = 7.5 Hz, 2H), 7.64 (d, J = 6.4 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H),7.42-7.25 (m, 3H), 7.28 (s, 1H), 7.15 (t, J = 8.1 Hz, 2H), 7.10-7.00 (m,3H), 7.00-6.88 (m, 2H), 6.85 (d, J = 7.8 Hz, 1H), 6.67 (dd, J = 7.8, 2.8Hz, 1H), 6.06 (s, 1H), 5.29-5.05 (m, 3H), 4.62 (d, J = 11.6 Hz, 1H),4.45-4.31 (m, 4H), 4.26 (t, J = 7.3 Hz, 1H), 3.97 (s, 1H), 3.71-3.57 (m,2H), 3.52-3.45 (m, 3H), 3.39-3.18 (m, 3H), 3.10 (d, J = 17.5 Hz, 1H),3.00-2.61 (m, 8H), 2.32 (d, J = 13.2 Hz, 1H), 2.25-2.16 (m, 2H), 2.10(d, J = 9.4 Hz, 2H), 1.75 (s, 2H), 1.65 (d, J = 9.1 Hz, 2H), 1.24 (d, J= 6.3 Hz, 3H). I51 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[5-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]pentyl]phenyl) methoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1014.3  (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.90(d, J = 7.6 Hz, 2H), 7.84 (d, J = 9.3 Hz, 1H), 7.76-7.72 (m, 3H), 7.43(t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.18-7.15 (m, 3H), 7.11(d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.7 Hz, 2H), 7.00-6.91 (m, 3H), 6.85(dd, J = 6.0, 2.9 Hz, 1H), 6.69 (s, 1H), 5.37 (dd, J = 12.5, 5.4 Hz,1H), 5.06 (d, J = 9.7 Hz, 1H), 4.46-4.35 (m, 2H), 4.27 (dd, J = 12.1,7.8 Hz, 2H), 3.78 (s, 2H), 3.48-3.37 (m, 2H), 3.32 (s, 3H), 3.07 (s,1H), 3.13-2.98 (m, 1H), 2.88 (s, 2H), 2.88 (d, J = 15.7 Hz, 1H),2.77-2.66 (m, 1H), 2.65 (s, 1H), 2.57 (t, J = 7.7 Hz, 2H), 2.11-2.08 (m,3H), 2.01 (s, 2H), 1.79 (s, 1H), 1.62 (s, 6H), 1.41 (t, J = 7.6 Hz, 2H),1.08 (d, J = 6.2 Hz, 3H). I52 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-([5-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]pentyl]oxy)propyl] phenyl]methoxy)pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1072.8  (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.90(d, J = 7.6 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.84-7.63 (m, 3H), 7.43(t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.19-7.15 (m, 3H), 7.13-7.04 (m, 3H), 7.03 (d, J = 6.0 Hz, 2H), 6.98 (t, J = 8.7 Hz, 2H), 6.86(d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 5.33 (dd, J = 12.7, 5.3 Hz, 1H), 5.06(d, J = 11.1 Hz, 1H), 4.40 (s, 2H), 4.28 (dd, J = 12.3, 6.8 Hz, 2H),4.13 (s, 1H), 3.78 (s, 1H), 3.45 (d, J = 6.0 Hz, 2H), 3.36- 3.33 (m,3H), 3.07 (d, J = 16.2 Hz, 2H), 2.92-2.81 (m, 2H), 2.72-2.54 (m, 6H),2.08 (s, 1H), 2.02 (s, 2H), 1.98 (d, J = 6.0 Hz, 2H), 1.76 (t, J = 7.6Hz, 4H), 1.66-1.50 (m, 6H), 1.36 (d , J = 7.7 Hz, 2H), 1.08 (d, J = 6.2Hz, 3H). I53 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-([5-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-4-yl]pentyl]oxy)propyl] phenyl]methoxy)pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1072.7  (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.90(d, J = 7.4 Hz, 2H), 7.83 (d, J = 9.6 Hz, 1H), 7.79-7.70 (m, 3H), 7.43(t, J = 7.3 Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.21-7.15 (m, 3H), 7.14-7.02 (m, 4H), 6.97-6.96 (m, 3H), 6.88 (s, 1H), 6.69 (s, 1H), 5.36 (d, J= 7.6 Hz, 1H), 5.06 (d, J = 9.6 Hz, 1H), 4.41 (s, 2H), 4.28-4.24 (m,3H), 4.13 (s, 1H), 3.78 (s, 2H), 3.55 (s, 3H), 3.38- 3.32 (m, 3H),2.94-2.86 (m, 3H), 2.84 (s, 2H), 2.64 (s, 3H), 2.61-2.56 (m, 3H),2.09-2.07 (m, 4H), 1.77 (s, 3H), 1.68-1.45 (m, 6H), 1.45 (d, J = 7.2 Hz,2H), 1.08 (d, J = 6.2 Hz, 3H). I54 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[4-[2-([[(2S,4R)-1-[(2S)-2- [(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5- yl)phenoxy]butyl]phenyl) methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1273.8  (400 MHz, DMSO-d₆) δ8.98 (d, J = 3.7 Hz, 1H), 8.48 (s, 1H), 7.89 (s, 2H), 7.84 (s, 1H),7.76-7.73 (m, 3H), 7.45-7.41 (m, 3H), 7.36-7.34 (m, 5H), 7.17-7.14 (m,7H), 7.04-6.99 (m, 4H), 6.94 (s, 2H), 6.68 (s, 1H), 5.16 (s, 1H), 5.05(d, J = 11.1 Hz, 1H), 4.60 (d, J = 9.0 Hz, 1H), 4.52 (s, 1H), 4.40 (s,2H), 4.35 (s, 1H), 4.28-4.27 (m, 4H), 4.17-4.05 (m, 3H), 3.78 (s, 2H),3.62 (d, J = 10.2 Hz, 2H), 3.44-3.43 (m, 3H), 2.85 (d, J = 16.5 Hz, 1H),2.65-2.64 (m, 3H), 2.46-2.44 (m, 4H), 2.12-2.05 (m, 4H), 1.79-1.72 (m,3H), 1.35 (s, 1H), 1.22 (s, 1H), 1.07 (s, 3H), 0.96 (s, 9H). I55 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[5-[2-([[(2S,4R)-1-[(2S)-2- [(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5- yl)phenoxy]pentyl] phenyl)methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1287.9  (400 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.6 Hz,2H), 7.83 (d, J = 9.2 Hz, 1H), 7.79-7.69 (m, 3H), 7.47-7.26 (m, 6H),7.18-7.12 (m, 5H), 7.06-6.98 (m, 4H), 6.95 (d, J = 7.6 Hz, 2H), 6.68 (s,1H), 5.17 (d, J = 3.6 Hz, 1H), 5.06 (d, J = 11.3 Hz, 1H), 4.60 (d, J =9.2 Hz, 1H), 4.53 (t, J = 8.2 Hz, 1H), 4.43-4.28 (m, 3H), 4.30-4.19 (m,3H), 4.13 (s, 1H), 4.05 (t, J = 6.3 Hz, 2H), 3.78 (s, 1H), 3.70-3.55 (m,2H), 3.45 (d, J = 5.9 Hz, 1H), 3.06 (d, J = 13.1 Hz, 2H), 2.86 (d, J =16.8 Hz, 1H), 2.59 (t, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.08 (s, 1H),2.08-2.04 (m, 3H), 1.83-1.75 (m, 3H), 1.63 (d, J = 7.4 Hz, 2H), 1.49 (d,J = 7.6 Hz, 1H), 1.42-1.33 (m, 1H), 1.26-1.19 (m, 2H), 1.08 (d, J = 6.2Hz, 3H), 1.01 (s, 2H), 0.96 (s, 9H). I56 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[2-(2-[2-[2-([[(2S,4R)-1- [(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5- yl)phenoxy]ethoxy] ethoxy)ethoxy]propyl]phenyl)methoxy]pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M/2 + 1)]⁺ = 696.9 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.47 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.83 (d, J =9.2 Hz, 1H), 7.79-7.69 (m, 3H), 7.47-7.34 (m, 3H), 7.36-7.25 (m, 2H),7.18-7.14 (m, 3H), 7.10 (d, J = 7.8 Hz, 2H), 7.08-7.01 (m, 4H), 6.97(dd, J = 7.7, 1.6 Hz, 2H), 6.68 (s, 1H), 5.16 (d, J = 3.6 Hz, 1H), 5.06(d, J = 10.5 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.52 (t, J = 8.2 Hz,1H), 4.38 (d, J = 13.7 Hz, 4H), 4 35-4.09 (m, 7H), 3.80 (d, J = 9.4 Hz,1H), 3.80 (s, 3H), 3.70-3.60 (m, 4H), 3.58 (d, J = 1.8 Hz, 1H), 3.59-3.50 (m, 4H), 3.48 (s, 1H), 3.49-3.40 (m, 3H), 3.37 (t, J = 6.5 Hz, 2H),3.05 (dd, J = 18.6, 12.6 Hz, 2H), 2.86 (d, J = 16.6 Hz, 1H), 2.58 (t, J= 7.7 Hz, 2H), 2.46 (s, 3H), 2.08 (s, 3H), 1.92 (tt, J = 9.5, 4.5 Hz,1H), 1.81-1.72 (m, 3H), 1.55 (d, J = 11.4 Hz, 1H), 1.43- 1.31 (m, 1H),1.22 (dd, J = 8.2, 3.3 Hz, 2H), 1.08 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H).I57 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[1-[2-([[(2S,4R)-1-[(2S)-2- [(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5-yl)phenoxy]- 3,6,9,12- tetraoxapentadecan-15- yl]phenyl)methoxy] pentan-3-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M/2 + 1)]⁺ = 718.9 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.47 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.83 (d, J =9.3 Hz, 1H), 7.79-7.39 (m, 3H), 7.47-7.25 (m, 6H), 7.20-7.01 (m, 9H),6.97 (dd, J = 7.7, 1.8 Hz, 2H), 6.68 (s, 1H), 5.16 (d, J = 3.6 Hz, 1H),5.06 (d, J = 10.9 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.52 (t, J = 8.2Hz, 1H), 4.41-4.35 (m, 3H), 4.32- 4.21 (m, 4H), 4.18 (t, J = 4.7 Hz,2H), 3.79 (d, J = 9.2 Hz, 1H), 3.79 (s, 3H), 3.69-3.52 (m, 5H),3.55-3.44 (m, 8H), 3.36 (t, J = 6.5 Hz, 2H), 3.11-2.98 (m, 2H), 2.86 (d,J = 16.8 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.08 (s, 1H),2.03 (s, 1H), 1.92 (d, J = 3.3 Hz, 1H), 1.79-7.71 (m, 3H), 1.56 (s, 1H),1.45-1.35 (m, 1H), 1.23 (d, J = 8.6 Hz, 2H), 1.07 (d, J = 6.2 Hz, 3H),1.00 (s, 2H), 0.96 (s, 9H). I58 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[1-[2-([[(2S,4R)-1-[(2S)-2- [(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5-yl)phenoxy]- 3,6,9,12,15- pentaoxaoctadecan-18- yl]phenyl)methoxy] pentan-3-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M/2 + 1)]⁺ = 740.9 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.47 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.83 (d, J =9.2 Hz, 1H), 7.81-7.68 (m, 3H), 7.47-7.20 (m, 6H), 7.17 (d, J = 8.2 Hz,3H), 7.11 (d, J = 7.8 Hz, 2H), 7.05 (m, 4H), 6.97 (dd, J = 7.8, 1.7 Hz,2H), 6.68 (s, 1H), 5.16 (d, J = 3.6 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H),4.60 (d, J = 9.2 Hz, 1H), 4.52 (t, J = 8.2 Hz, 1H), 4.38 (d, J = 15.8Hz, 3H), 4.33-4.25 (m, 2H), 4.27-4.21 (m, 1H), 4.21-4.11 (m, 2H),3.82-3.75 (m, 3H), 3.70-3.59 (m, 3H), 3.55 (dd, J = 5.9, 3.5 Hz, 2H),3.50-3.41 (m, 2H), 3.41-3.29 (m, 4H), 3.15-3.07 (m, 1H), 3.05 (s, 1H),2.86 (d, J = 16.8 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.47-2.46 (m, 4H),2.09 (m, 6H), 2.08 (s, 2H), 2.04 (t, J = 9.8 Hz, 2H), 1.93 (tt, J = 8.2,4.6 Hz, 1H), 1.81-1.74 (m, 3H), 1.55 (d, J = 10.0 Hz, 1H), 1.43- 1.31(m, 2H), 1.22 (dd, J = 8.9, 3.1 Hz, 2H), 1.08 (d, J = 6.2 Hz, 3H), 1.01(s, 2H), 0.96 (s, 9H). I59 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[3-[2-([[(2S,4R)-1-[(2S)-2- [(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5- yl)phenoxy]propyl] phenyl)methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1259.9  (400 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.52 (t, J = 6.0 Hz, 1H), 7.85-7.82 (m, H),7.78-7.52 (m, 4H), 7.44-7.40 (m, 3H), 7.38-7.29 (m, 2H), 7.29 (s, 1H),7.19-7.17 (m, 6H), 7.06-6.89 (m, 6H), 6.69 (s, 1H), 5.17 (d, J = 3.6 Hz,1H), 5.05 (d, J = 11.2 Hz, 1H), 4.61 (d, J = 9.2 Hz, 1H), 4.53 (t, J =8.1 Hz, 1H), 4.41 (s, 2H), 4.36-4.23 (m, 3H), 4.13 (s, 1H), 4.05 (t, J =6.0 Hz, 2H), 3.79 (s, 1H), 3.70-3.57 (m, 2H), 3.08 (s, 2H), 3.02 (d, J =16.5 Hz, 1H), 2.89- 2.73 (m, 4H), 2.48 (s, 1H), 2.46-2.45 (m, 3H), 2.08(s, 2H), 1.92 (dd, J = 16.6, 7.9 Hz, 1H), 1.78 (s, 1H), 1.55 (s, 1H),1.43-1.29 (m, 2H), 1.22 (dd, J = 8.5, 3.4 Hz, 2H), 1.08 (d, J = 6.2 Hz,3H), 0.97 (s, 9H), 0.96 (s, 2H). I60 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(3-[2-[2-([[(2S,4R)-1-[(2S)- 2-[(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5- yl)phenoxy]ethoxy] propyl)phenyl]methoxy]pentan-3- yl]carbamoyl]-12-oxo-1- 1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1303.8  (400 MHz,CDCl₃) δ 8.76 (s, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.64 (s, 2H), 7.41 (t,J = 7.4 Hz, 2H), 7.35 (m, 4H), 7.26 (s, 1H), 7.16 (d, J = 7.7 Hz, 2H),7.15-7.05 (m, 4H), 6.98 (d, J = 7.7 Hz, 1H), 6.91 (s, 1H), 5.95 (s, 1H),5.20 (s, 1H), 5.03 (s, 1H), 4.68-4.55 (m, 3H), 4.51-4.38 (m, 5H), 4.35(s, 1H), 4.30-4.14 (m, 3H), 4.04-3.90 (m, 2H), 3.82 (s, 2H), 3.68-3.53(m, 4H), 3.36 (s, 1H), 2.69 (t, J = 7.7 Hz, 2H), 2.56 (s, 3H), 2.38-2.35(m, 4H), 2.08-2.07 (m, 3H), 1.94 (d, J = 7.3 Hz, 3H), 1.37-1.28 (m, 3H),1.24 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H). I61 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-([4-[3-(2-[2-[2-([[(2S,4R)-1- [(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]-4- hydroxypyrrolidin-2- yl]formamido]methyl)-5-(4-methyl-1,3- thiazol-5 yl)phenoxy]ethoxy] ethoxy)propyl]phenyl]methoxy)pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1348.0  (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.49(s, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 10.0 Hz, 1H), 7.80-7.72(m, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.33 (dd, J = 15.9, 8.3 Hz, 2H),7.19- 7.07 (m, 5H), 7.06-7.05 (m, 3H), 6.97 (d, J = 7.7 Hz, 2H), 6.69(s, 1H), 5.17 (s, 1H), 5.06 (d, J = 11.5 Hz, 1H), 4.60 (d, J = 9.2 Hz,1H), 4.53 (d, J = 8.1 Hz, 1H), 4.40 (s, 2H), 4.35 (s, 1H), 4.32-4.27 (m,3H), 4.27-4.25 (m, 6H), 4.20 (s, 2H), 3.81 (s, 3H), 3.65-3.61 (m, 3H),3.52 (s, 1H), 3.43-3.35 (m, 2H), 3.05 (s, 1H), 2.85 (d, J = 17.1 Hz,1H), 2.59-2.54 (m, 4H), 2.46 (s, 3H), 2.08-2.07 (m, 6H), 1.91 (s, 3H),1.76 (s, 2H), 1.38 (s, 1H), 1.34 (s, 1H), 1.23 (d, J = 9.2 Hz, 2H), 1.08(d, J = 6.2 Hz, 3H), 0.96 (s, 9H). I62 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[4-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]butyl]phenyl)methoxy] pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1000.6  (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.88-7.82 (m, 3H), 7.81-7.67 (m, 3 H), 7.50-7.38 (m, 3H), 7.34 (t, J =7.4 Hz, 2H), 7.19-7.12 (m, 4H), 7.10 (d, J = 7.9 Hz, 1H), 7.08-6.89 (m,4H), 6.89-6.81 (m, 1H), 6.76-6.42 (m, 1H), 5.38-5.33 (m, 1H), 5.12-5.05(m, 1H), 4.40-4.38 (m, 3H), 4.26-4.21 (m, 5 H), 4.16-4.07 (m, 1H),3.79-3.70 (m, 2H), 3.49-3.37 (m, 2H), 3.31 (s, 3H), 3.16-3.06 (m, 2H),2.97-2.76 (m, 2H), 2.76-2.54 (m, 3H), 2.15-1.99 (m, 4H), 1.76-1.71 (m,1H), 1.65-1.50 (m, 3 H), 1.26-1.21 (m, 2H), 1.03 (d, J = 6.2 Hz, 3H).I63 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[(4-[6-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]hexyl]phenyl)methoxy] pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1028.6  (400 MHz, CDCl₃) δ 7.84-7.69 (m, 6H), 7.67(d, J = 7.5 Hz, 2H), 7.48-7.33 (m, 4H), 7.32-7.27 (m, 4H), 7.22-7.09 (m,5H), 6.89-6.81 (m, 1H), 6.37- 6.26 (m, 1H), 6.11 (s, 2H), 5.40-5.34 (m,1H), 5.33-5.31 (m, 4H), 5.26-4.98 (m, 1H), 4.93-4.54 (m, 1H), 4.53-4.31(m, 5H), 4.27 (t, J = 7.5 Hz, 1H), 3.76-3.50 (m, 2H), 3.48 (s, 3H), 3.42(s, 1H), 3.25-3.04 (m, 3H), 2.97-2.69 (m, 1H), 2.76-2.60 (m, 2H),2.43-2.16 (m, 2H), 2.09 (m, 1H), 1.99-1.71 (m, 1H), 1.72-1.61 (m, 2H),1.45-1.30 (m, 4H), 0.96 (d, J = 6.2 Hz, 3H). I64 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-4-[[4-(4-[[(2S)-1-(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]-1- (methylcarbamoyl)pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1213.9  (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.93-7.84 (m, 4H),7.80-7.70 (m, 3H), 7.57 (d, J = 4.9 Hz, 1H), 7.46-7.29 (m, 8H), 7.16 (d,J = 7.9 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H),7.01-6.93 (m, 1H), 5.13 (s, 1H), 5.05- 5.01 (m, 1H), 4.55 (d, J = 9.4Hz, 1H), 4.48-4.32 (m, 4H), 4.32-4.16 (m, 3H), 4.12 (d, J = 8.9 Hz, 1H),3.82-3.71 (m, 1H), 3.71-3.64 (m, 2H), 3.45-3.41 (m, 2H), 3.10-3.02 (m,2H), 2.84-2.81 (m, 1H), 2.57-2.54 (m, 6H), 2.45 (s, 3H), 2.37-2.27 (m,1H), 2.18-2.00 (m, 5H), 1.92-1.90 (m, 1H), 1.54-1.48 (m, 4H), 1.36-1.31(m, 4H), 1.07 (d, J = 6.2 Hz, 3H), 0.94 (s, 9H). I65 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1213.9  (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57(t, J = 6.1 Hz, 1H), 7.93-7.84 (m, 4H), 7.8-7.70 (m, 3H), 7.57 (d, J =4.9 Hz, 1H), 7.45-7.30 (m, 8H), 7.16 (d, J = 7.9 Hz, 2H), 7.10 (d, J =7.9 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.00- 6.93 (m, 1H), 6.88 (s, 1H),5.13 (s, 1H), 5.05-5.01 (m, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.48-4.32 (m,4H), 4.32-4.17 (m, 3H), 4.12 (d, J = 8.9 Hz, 1H), 3.81-3.71 (m, 1H),3.71-3.64 (m, 2H), 3.43-3.41 (m, 2H), 3.07-3.02 (m, 2 H), 2.84-2.81 (m,1H), 2.60-2.55-2.52 (m, 6H), 2.45 (s, 3H), 2.37-2.27 (m, 1H), 2.20-1.99(m, 4H), 1.92-1.90 (m, 1H), 1.54-1.48 (m, 4H), 1.36-1.32 (m, 4H), 1.07(d, J = 6.2 Hz, 3H), 0.94 (s, 9H). I66 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]cyclopropyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1225.2  (400 MHz,DMSO-d₆) δ 8.97 (s, 1H), 8.81 (s, 1H), 7.98-7.81 (m, 4H), 7.80- 7.70 (m,3H), 7.54 (s, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.38-7.26 (m, 5H),7.24-7.02 (m, 6H), 7.01-6.93 (m, 1H), 6.70 (s, 1H), 5.13 (d, J = 3.4 Hz,1H), 5.10-5.02 (m, 1H), 4.56 (d, J = 9.4 Hz, 1H), 4.40 (d, J = 16.4 Hz,1H), 4.40-4.38 (m, 3H), 4.36 (s, 1H), 4.32- 4.23 (m, 2H), 4.10-4.08 (m,2H), 3.79 (s, 1H), 3.65-3.62 (m, 2H), 3.48-3.37 (m, 2H), 3.18 (d, J =5.2 Hz, 5H), 3.08-3.06 (m, 1H), 2.86 (d, J = 16.6 Hz, 1H), 2.55 (d, J =7.1 Hz, 2H), 2.44 (s, 3H), 2.09-2.07 (m, 3H), 1.94-1.82 (m, 1H), 1.79(s, 1H), 1.54-1.51 (m, 8 H), 1.29-1.15 (m, 3H), 1.08 (d, J = 6.1 Hz,3H), 0.94 (s, 9H). I67 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pent-1- yn-1- yl)phenyl]methoxy]pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1209.2  (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.58-8.56 (m, 1H), 7.99 (d, J = 9.3 Hz, 1H),7.91-7.89 (m, 3H), 7.77-7.75 (m, 4H), 7.40-7.33 (m, 9H), 7.25 (d, J =8.0 Hz, 1H), 7.20-7.10 (m, 1H), 7.09-7.01 (m, 3H), 6.98-6.95 (m, 1H),6.71 (s, 1H), 5.15 (s, 1H), 5.10-5.01 (m, 1H), 4.62-4.40 (m, 3H),4.40-4.20 (m, 4H), 4.20-3.99 (m, 4H), 3.81-3.68 (m, 2H), 3.52-3.48 (m,2H), 3.19 (m, 10H), 2.84 (d, J = 16.2 Hz, 1H), 2.49 (s, 3H), 2.20-1.88(m, 4H), 1.88- 1.49 (m, 3H), 1.10 (d, J = 6.1 Hz, 3H), 0.97 (s, 9H).I68 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(4-[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]but-1- yn-1- yl)phenyl]methoxy]pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1195.2  (400 MHz,CD₃OD) δ 7.81 (d, J = 7.5 Hz, 2H), 7.74-7.54 (m, 4H), 7.50-7.19 (m,10H), 7.10-7.05 (m, 4H), 5.26- 5.07 (m, 1H), 4.69-4.67 (m, 1H), 4.61-4.46 (m, 3H), 4.44-4.18 (m, 9H), 4.03-3.78 (m, 2H), 3.65-3.48 (m, 1H),3.35-3.17 (m, 7H), 2.94 (d, J = 16.5 Hz, 1H), 2.72-2.69 (m, 1H),2.52-2.47 (m, 2H), 2.22-2.16 (m, 5H), 2.02 (d, J = 7.6 Hz, 1H),1.64-1.59 (m, 1H), 1.18-1.16 (m, 3H), 1.04 (s, 9H). I69 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]propoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate  896.3  (400 MHz, CD₃OD) δ 7.81 (d, J = 7.5 Hz,2H), 7.72-7.69 (m, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.4 Hz,2H), 7.11-6.91 (m, 6H), 5.31-5.27 (m, 1H), 5.22-5.10 (m, 1H), 4.38-4.35(m, 1H), 4.33-4.29 (d, J = 10.1 Hz, 2H), 4.28-4.20 (m, 1H), 3.92 (d, J =11.9 Hz, 1H), 3.51-3.49 (m, 1H), 3.47-3.35 (m, 7H), 3.09-3.05 (m, 1H),2.95-2.86 (m, 1H), 2.84-2.70 (m, 4H), 2.27- 2.24 (m, 5H), 2.18-2.10 (m,1H), 2.04- 2.02 (m, 1H), 1.98-1.97 (m, 1H), 1.87 (t, J = 7.3 Hz, 2H),1.15 (d, J = 6.4 Hz, 3H). I70 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[3-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1199.2  (400 MHz,CD₃OD) δ 8.87 (s, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 8.2 Hz,2H), 7.46 (d, J = 8.0 Hz, 2H), 7.43-7.36 (m, 4H), 7.32-7.28 (m, 2H),7.19 (d, J = 8.5 Hz, 2H), 7.14-6.97 (m, 5H), 5.11-5.09 (m, 1H),4.68-4.58 (m, 1H), 4.58-4.51 (m, 5H), 4.41-4.28 (m, 3H), 4.24 (t, J =7.0 Hz, 1H), 3.94-3.92 (m, 2H), 3.80-3.78 (m, 1H), 3.68-3.40 (m, 2H),3.37 (s, 1H), 3.17- 3.14 (m, 3H), 3.08-2.87 (m, 1H), 2.69- 2.60 (m, 3H),2.47 (s, 3H), 2.37-2.14 (m, 2H), 2.10-2.08 (m, 1H), 1.71-1.62 (m, 6H),1.22-1.17 (m, 4H), 1.04- 0.98 (m, 11H). I71 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[2-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1213.8  (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.89-7.82 (m, 4H),7.75-7.71 (m, 3H), 7.47-7.29 (m, 9H), 7.25-6.92 (m, 7H), 6.72 (s, 1H),5.18-4.95 (m, 2H), 4.58-4.32 (m, 7H), 4.32-4.07 (m, 5H), 3.85-3.64 (m,3H), 3.55-3.38 (m, 1H), 3.19-2.98 (m, 1H), 2.85 (d, J = 16.7 Hz, 1H),2.55-2.52 (m, 2H), 2.45 (s, 3H), 2.35- 2.00 (m, 6H), 1.95-1.86 (m, 1H),1.61- 1.42 (m, 5H), 1.36 (s, 1H), 1.27-1.24 (m, 2H), 1.15-1.00 (m, 5H),0.93 (s, 9 H). I72 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-7-(2-[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]ethyl) naphthalen-2- yl]methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1221.60 (400 MHz, DMSO-d₆) δ8.98 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H),7.91-7.86 (m, 3H), 7.83- 7.67 (m, 6H), 7.64 (s, 1H), 7.45-7.38 (m, 6H),7.35-7.33 (m, 3H), 7.18 (s, 1H), 7.07-7.00 (m, 1H), 6.95-6.93 (m, 2H),6.71 (s, 1H), 5.16 (d, J = 3.6 Hz, 1H), 5.09-5.01 (m, 1H), 4.62-4.58 (m,3H), 4.44-4.41 (m, 2H), 4.36 (s, 1H), 4.31-4.17 (m, 3H), 4.12-4.09 (m,3H), 3.82-3.79 (m, 1H), 3.69-3.67 (m, 2H), 3.52-3.41 (m, 1H), 3.19-3.15(m, 5H), 3.13-2.93 (m, 2H), 2.84-2.67 (m, 2H), 2.44 (s, 3H), 2.10-2.00(m, 4H), 1.92-1.90 (m, 1H), 1.83-1.78 (m, 2H), 1.60-1.56 (d, 1H), 1.11(d, J = 6.2 Hz, 3H), 0.88 (s, 9H). I73 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[6-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) naphthalen-2- yl]methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1235.95 Used in the next stepwithout further purification I74 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4R)-1- carbamoyl-4-[[5-(2-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]ethyl) naphthalen-2- yl]methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1221.30 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H), 8.07 (d, J = 9.3 Hz, 1H), 7.99(d, J = 8.7 Hz, 1H), 7.91-7.87 (m, 4H), 7.78-7.73 (m, 6H), 7.43-7.36 (m,7H), 7.21-7.19 (m, 1H), 7.13-7.11 (d, J = 7.2 Hz, 1H), 7.09- 6.93 (m,4H), 6.74-6.72 (m, 1H), 5.18 (d, J = 3.5 Hz, 1H), 5.07-5.03 (m, 2H),4.64-4.61 (m, 2H), 4.54-4.34 (m, 2H), 4.29-4.21 (m, 4H), 4.15-4.11 (m,1H), 3.87-3.85 (m, 1H), 3.69-3.67 (m, 2H), 3.52-3.49 (m, 1H), 3.36-3.31(m, 2H), 3.19-2.94 (m, 4H), 2.83-3.81 (m, 2H), 2.76-2.67 (m, 1H),2.63-2.54 (m, 1H), 2.45 (s, 3H), 2.10-2.06 (s, 4H), 1.97-1.76 (m, 2H),1.62-1.59 (m, 1H), 1.13 (d, J = 6.1 Hz, 3H), 0.94 (s, 9H). I75 

9H-fluoren-9-ylmethyl N-[(2S,11S)-2- [[(3S,4S)-1- carbamoyl-4-[[5-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) naphthalen-2- yl]methoxy]pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1235.45 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.99 (t, J = 8.1 Hz, 2H),7.92-7.86 (m, 4H), 7.76- 7.72 (m, 6H), 7.47-7.27 (m, 9H), 7.19 (s, 1H),7.14-6.88 (m, 3H), 6.72 (s, 1H), 5.13 (d, J = 3.6 Hz, 1H), 5.06 (d, J =10.3 Hz, 1H), 4.63-4.60 (m, 3H), 4.45-4.40 (m, 2H), 4.37-3.35 (m, 1H),4.3-4.18 (m, 4H), 4.12-4.08 (m, 2H), 3.85-3.83 (m, 1H), 3.72-3.63 (m, 2H), 3.52-3.50 (m, 1H), 3.45-3.36 (m, 1H), 3.14-2.96 (m, 3H), 2.79 (d, J= 17.0 Hz, 1H), 2.44 (s, 3H), 2.42-2.25 (m, 1H), 2.10-2.03 (m, 6H),1.98-1.74 (m, 4H), 1.60-1.58 (m, 1H), 1.12 (d, J = 6.3 Hz, 3H), 0.96 (s,9H). I76 

9H-fluoren-9- ylmethyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-([4-[(1E)-5-[[(2S)-1- [(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pent-1- en-1- yl]phenyl]methoxy)pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1121.58 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.58 (s, 1H), 7.91-7.88 (m, 4H), 7.75 (t, J =6.9 Hz, 3H), 7.46-7.35 (m, 5H), 7.35-7.29 (m, 3H), 7.22-7.18 (m, 4 H),7.05 (d, J = 7.8 Hz, 2H), 6.99-6.97 (m, 1H), 6.71 (s, 1H), 6.42-6.27 (m,1H), 5.77 (s, 1H), 5.15 (d, J = 3.6 Hz, 1H), 5.06-5.04 (m, 1H), 4.57 (d,J = 9.2 Hz, 1H), 4.49-4.39 (m, 4H), 4.38- 4.36 (m, 1H), 4.26 (d, J = 7.5Hz, 2H), 3.67 (s, 2H), 3.45-3.4 (m, 1H), 3.32 (s, 11H), 2.82 (d, J =16.6 Hz, 1H), 2.45 (s, 3H), 2.33 (s, 1H), 2.17 (m, 2H), 2.07 (d, J =14.7 Hz, 5H), 1.93- 1.88 (m, 1H), 1.69-1.66 (m, 1H), 1.26- 1.22 (m, 1H),1.08 (d, J = 6.2 Hz, 3 H), 0.95 (s, 9H) I77 

9H-fluoren-9- ylmethyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-([4-[(1E)-4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]but-1- en-1- yl]phenyl]methoxy)pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1197.45 (400 MHz,CDCl₃) δ 8.70 (s, 1H), 8.03 (s, 1H), 7.76 (d, J = 7.6 Hz, 4H), 7.61 (d,J = 7.4 Hz, 4H), 7.40 (t, J = 7.4 Hz, 4H), 7.33-7.29 (m, 9H), 7.06-7.02(m, 7H), 6.25-6.21 (m, 1H), 5.30 (s, 3H), 4.55-4.52 (m, 2H), 4.38 (d, J= 7.5 Hz, 4H), 4.25-4.21 (m, 2H), 4.03 (d, J = 10.9 Hz, 1H), 3.52-3.42(m, 2H), 3.33-3.30 (m, 3H), 3.11 (d, J = 18.4 Hz, 4H), 2.96 (s, 1H),2.89 (d, J = 0.7 Hz, 1H), 2.49 (s, 3H), 2.33-2.30 (m, 1H), 2.16 (d, J =12.2 Hz, 2H), 2.06- 2.02 (m, 2H), 1.25 (s, 2H), 1.18 (d, J = 6.4 Hz,3H), 0.89 (s, 9H). I78 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]piperidin- 1- yl)phenyl]methoxy]pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1105.38 (400 MHz,DMSO-d₆) δ 9.00 (d, J = 1.8 Hz, 1H), 8.64-8.55 (m, 1H), 7.88 (d, J = 9.4Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.45-7.38 (m, 5H), 7.16 (s, 1 H),7.09 (s, 2H), 7.05 (d, J = 6.8 Hz, 2H), 6.96 (s, 1H), 6.85 (d, J = 8.5Hz, 1H), 6.68 (s, 1H), 5.76 (s, 3H), 5.15- 5.01 (m, 2H), 4.62-4.53 (m,1H), 4.50- 4.41 (m, 3H), 4.39-4.30 (m, 3H), 4.04 (s, 1H), 3.68 (dd, J =18.0, 10.6 Hz, 5H), 2.64 (d, J = 12.1 Hz, 2H), 2.46 (s, 3H), 2.10-2.02(m, 5H), 1.94-1.88 (m, 1H), 1.85-1.76 (m, 3H), 1.69-1.62 (m, 2H), 1.39(s, 9H), 1.24 (s, 1H), 1.14 (d, J = 6.3 Hz, 3H), 1.10-1.04 (m, 4H), 0.96(s, 9H). I79 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-([4-[4-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methyl) piperidin-1- yl]phenyl]methoxy)pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1118.57 (400 MHz,CD₃OD) δ 8.89 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.46-7.42 (m, 2H),7.22-7.18 (m, 2H), 7.08 (t, J = 8.2 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H),6.94-6.89 (m, 2H), 5.11 (dd, J = 10.9, 3.4 Hz, 1H), 4.70-4.65 (m, 1H),4.60- 4.56 (m, 1H), 4.53 (d, J = 7.2 Hz, 2H), 4.49-4.39 (m, 3H), 4.25(dd, J = 8.5, 3.7 Hz, 1H), 4.00-3.92 (m, 2H), 3.83 (dd, J = 10.9, 3.9Hz, 1H), 3.67 (d, J = 13.6 Hz, 2H), 3.55 (dd, J = 6.4, 4.5 Hz, 1H), 3.45(dd, J = 16.7, 10.9 Hz, 1H), 3.15 (q, J = 6.7, 5.7 Hz, 2 H), 2.96 (dd, J= 16.6, 3.3 Hz, 1H), 2.76-2.63 (m, 3H), 2.49 (s, 3H), 2.30-2.25 (m, 4H),2.21 (d, J = 6.3 Hz, 2H), 2.13-2.10 (m, 1H), 2.01-1.89 (m, 2H), 1.82 (d,J = 13.0 Hz, 2H), 1.72-1.62 (m, 1H), 1.52-1.44 (m, 12H), 1.18 (d, J =6.4 Hz, 3H), 1.07 (s, 9H). I80 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-([4-[4-(2-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]ethyl) piperidin-1- yl]phenyl]methoxy)pentan-3-yl]carbamoyl]- 12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1132.90 (400 MHz,CD₃OD) δ 8.89 (s, 1H), 8.37 (s, 1H), 7.92 (dd, J = 15.1, 9.2 Hz, 1H),7.52-7.39 (m, 5H), 7.20 (d, J = 8.0 Hz, 2H), 7.08 (t, J = 8.2 Hz, 2H),7.01 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 5.11 (dd, J = 10.9,3.4 Hz, 1H), 4.71-4.64 (m, 1H), 4.61-4.55 (m, 2H), 4.54-4.51 (m, 1H),4.44 (d, J = 8.9 Hz, 2H), 4.42-4.33 (m, 1H), 4.27-4.23 (m, 1H),4.00-3.92 (m, 2H), 3.83 (dd, J = 11.0, 3.9 Hz, 1H), 3.71- 3.64 (m, 3H),3.60-3.51 (m, 1H), 3.51- 3.39 (m, 1H), 3.22-3.08 (m, 2H), 2.96 (dd, J =16.7, 3.3 Hz, 1H), 2.67 (t, J = 11.7 Hz, 2H), 2.49 (s, 3H), 2.37 (q, J =8.0 Hz, 2H), 2.31-2.15 (m, 4H), 2.14-2.07 (m, 1H), 2.06-1.94 (m, 1H),1.85 (d, J = 11.9 Hz, 2H), 1.73-1.57 (m, 2H), 1.48 (s, 9H), 1.44-1.29(m, 1H), 1.18 (d, J = 6.3 Hz, 3H), 1.07 (s, 9H). I81 

tert-butyl N-[(2S)-1- [(1R,2S,5S)-2- [[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-3- azabicyclo[3.1.0]hexan- 3-yl]-4-methyl-1-oxopentan-2- yl]carbamate 1071.30 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H),8.57 (t, J = 6.0 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 7.58 (d, J = 9.3 Hz,1H), 7.41 (q, J = 8.4 Hz, 4H), 7.24 (d, J = 7.8 Hz, 2H), 7.14 (d, J =7.8 Hz, 2 H), 7.05 (s, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.67 (s, 1H), 5.13(d, J = 3.5 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.50- 4.32 (m, 6H),4.26-4.18 (m, 1H), 4.12- 4.06 (m, 1H), 3.89-3.85 (m, 1H), 3.75-3.60 (m,2H), 3.53 (d, J = 9.6 Hz, 1H), 3.36-3.32 (m, 3H), 2.56-2.53 (m, 1H),2.45 (s, 3H), 2.33-2.30 (m, 1H), 2.22-1.99 (m, 4H), 1.95-1.86 (m, 2H),1.83-1.72 (m, 2H), 1.64-1.52 (m, 7H), 1.37 (s, 9H), 1.24-1.20 (m, 1H),1.08 (d, J = 6.2 Hz, 3H), 0.94 (s, 9H), 0.86 (d, J = 6.6 Hz, 6H),0.72-0.69 (m, 1H), 0.61-0.53 (m, 1H). I82 

9H-Fluoren-9- ylmethyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl-1-[[4-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]butan-2-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1199.45 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.92-7.85 (m, 4H),7.74 (q, J = 7.6, 7.2 Hz, 3H), 7.47-7.29 (m, 8H), 7.25-7.09 (m, 5H),7.08-6.91 (m, 3H), 6.72 (s, 1H), 5.11 (d, J = 3.6 Hz, 1H), 5.02 (dd, J =10.6, 2.9 Hz, 1H), 4.92 (p, J = 7.1 Hz, 1 H), 4.52 (d, J = 9.3 Hz, 1H),4.42 (d, J = 6.7 Hz, 3H), 4.35-4.15 (m, 4H), 4.15-4.06 (m, 1H), 3.83 (m,1H), 3.70- 3.53 (m, 2H), 3.21-2.94 (m, 2H), 2.94- 2.65 (m, 1H), 2.56 (d,J = 7.1 Hz, 1H), 2.46 (s, 3H), 2.36-2.23 (m, 1H), 2.08 (s, 12H),1.83-1.77 (m, 1H), 1.67- 1.43 (m, 4H), 1.38 (d, J = 6.9 Hz, 3H), 0.94(s, 9H). I83 

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-([[4-(3-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenyl]methyl]carbamoyl) propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1062.40 (400 MHz DMSO-d₆) δ8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.35 (t, J = 5.9 Hz, 1H), 8.20(d, J = 7.9 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H),7.39 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.12-7.08 (m, 4H), 7.08 (d, J =6.4 Hz, 2H), 6.98-6.96 (m, 2H), 6.76 (s, 1H), 5.16-5.08 (m, 2H), 4.56(d, J = 9.3 Hz, 1H), 4.47-4.40 (m, 2H), 4.36-4.34 (m, 1H), 4.24-4.20 (m,4H), 4.05 (d, J = 9.1 Hz, 1H), 3.68- 3.66 (m, 2H), 3.32-3.30 (m, 2H),3.10-30.6 (m, 2H), 3.02-2.96 (m, 2H), 2.45 (s, 3H), 2.28-2.17 (m, 2H),2.09- 2.01 (m, 6H), 1.93-1.91 (m, 1H), 1.78- 1.74 (m, 3H), 1.39 (s, 9H),0.95 (s, 9H) I84 

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-([[4-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methyl]carbamoyl) propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1076.60 (400 MHz, CD₃OD) δ 8.89(s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.20-6.98(m, 7H), 5.17 (dd, J = 10.9, 3.3 Hz, 1H), 4.66-4.45 (m, 5H), 4.40-4.19(m, 4H), 3.89 (s, 1H), 3.81 (dd, J = 11.0, 3.9 Hz, 1H), 3.56- 3.45 (m,1H), 3.37 (s, 3H), 3.21-3.08 (m, 1H), 2.69-2.57 (m, 3H), 2.49 (s, 3H),2.41-2.16 (m, 5H), 2.14-1.89 (m, 2H), 1.63 (s, 5H), 1.47 (s, 9H), 1.04(s, 9H) I85 

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-([[4-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]methyl]carbamoyl) propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1090.40 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.57 (m, J = 6.1 Hz, 1H), 8.35 (m, J = 5.8 Hz, 1H), 8.20(d, J = 7.9 Hz, 1 H), 7.86 (d, J = 9.3 Hz, 1H), 7.44-7.37 (m, 4H), 7.26(s, 1H), 7.13-7.03 (m, 7H), 6.97-6.95 (m, 2H), 6.76 (s, 1H), 5.15-5.08(m, 2H), 4.54 (d, J = 9.4 Hz, 1H), 4.47-4.40 (m, 2H), 4.35 (s, 1H),4.24-4.18 (m, 4H), 4.05-4.03 (m, 1H), 3.70-3.62 (m, 2H), 3.46-3.39 (m,1H), 3.12-2.92 (m, 3H), 2.45 (s, 3H), 2.28-2.24 (m, 1H), 2.15-1.99 (m,7H), 1.93-1.89 (m, 2H), 1.77-1.75 (m, 1H), 1.55-1.49 (m, 4H), 1.39 (s,9H), 1.28-1.24 (m, 2H), 0.93 (s, 9H) I86 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[3′-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methyl)- [1,1′-biphenyl]-4-yl]methoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1111.70 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.59(t, J = 6.1 Hz, 1H), 8.19 (d, J = 9.3 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H),7.61-7.55 (m, 3H), 7.51 (d, J = 7.8 Hz, 1H), 7.49-7.37 (m, 7H), 7.28 (d,J = 7.6 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.06-7.02 (m,2H), 6.96 (t, J = 7.4 Hz, 1H), 6.70 (s, 1H), 5.77 (s, 3H), 5.14-5.12 (m,1H), 5.08 (dd, J = 10.7, 2.8 Hz, 1H), 4.56 (d, J = 9.3 Hz, 1H),4.50-4.42 (m, 4H), 4.36 (s, 1H), 4.23 (dd, J = 15.9, 5.5 Hz, 1H), 4.06(t, J = 8.5 Hz, 1H), 3.84-3.82 (m, 1H), 3.76 (d, J = 13.8 Hz, 1H),3.70-3.62 (m, 2H), 3.57-3.46 (m, 3H), 3.10-2.99 (m, 1H), 2.87 (d, J =16.5 Hz, 1H), 2.46 (s, 3H), 2.15-2.04 (m, 3H), 1.95-1.88 (m, 1H),1.81-1.79 (m, 1H), 1.63-1.56 (m, 1H), 1.39 (s, 9H), 1.12 (d, J = 6.2 Hz,3H), 0.94 (s, 9H) I87 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[(4-[[(1r,3r)-3-[[(2S)-1- [(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]cyclobutyl] methyl]phenyl)methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1189.54 (400 MHz, DMSO-d₆) δ8.99 (d, J = 1.2 Hz, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 9.2 Hz,1H), 7.68 (t, J = 8.6 Hz, 1H), 7.45-7.35 (m, 4H), 7.16 (d, J = 7.9 Hz,3H), 7.10-7.02 (m, 5H), 7.00-6.93 (m, 1H), 6.68 (s, 1H), 5.14 (s, 1H),5.06 (dd, J = 10.8, 2.7 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.48-4.32 (m,5H), 4.22 (dd, J = 15.9, 5.5 Hz, 1H), 4.05 (t, J = 8.7 Hz, 1H), 3.79 (s,1H), 3.67 (s, 2H), 3.50-3.36 (m, 2H), 3.11-2.95 (m, 2H), 2.86 (d, J =16.6 Hz, 1H), 2.65 (dd, J = 33.6, 7.6 Hz, 2H), 2.45 (s, 3H), 2.43-2.32(m, 1H), 2.22-1.97 (m, 3H), 1.96-1.84 (m, 2H), 1.78 (q, J = 9.5 Hz, 2H),1.56 (dd, J = 17.1, 8.1 Hz, 1H), 1.40-1.38 (m, 11H), 1.25-1.23 (m, 1H),1.08 (d, J = 6.3 Hz, 3H), 0.93 (s, 9H) I88 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[(4-[[3-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methyl) cyclobutyl]methyl]phenyl)methoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1103.39 Used in the next step without furtherpurification I89 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-([4-[3-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methyl) cyclobutyl]phenyl] methoxy)pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1089.70 (400 MHz, CD₃OD) δ 8.89(d, J = 1.3 Hz, 1H), 8.11 (s, 1H), 7.48 (dd, J = 8.4, 2.6 Hz, 2H),7.48-7.39 (m, 2H), 7.29-7.13 (m, 4H), 7.09 (d, J = 7.3 Hz, 1H),7.07-6.95 (m, 2H), 5.12 (dt, J = 10.5, 3.0 Hz, 1H), 4.67 (d, J = 4.3 Hz,1H), 4.64-4.44 (m, 5H), 4.37 (dd, J = 15.5, 2.9 Hz, 1H), 4.28-4.21 (m,1H), 4.12 (q, J = 7.1 Hz, 1H), 4.00 (d, J = 6.3 Hz, 1H), 3.92 (d, J =10.9 Hz, 1H), 3.84-3.80 (m, 1H), 3.69-3.53 (m, 1H), 3.51-3.35 (m, 1H),3.23-3.05 (m, 2H), 3.01-2.97 (m, 1H), 2.78-2.54 (m, 1H), 2.49 (s, 3H),2.47-2.35 (m, 1H), 2.33-2.24 (m, 3H), 2.23-2.18 (m, 5H), 2.14-2.01 (m,2H), 1.88-1.84 (m, 1H), 1.71-1.67 (m, 1H), 1.57 (s, 1H), 1.48 (s, 9H),1.19 (s, 3H), 1.06 (s, 9H) I90 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoy-4-[(4-[[1-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]methyl) piperidin-4- yl]methyl]phenyl)methoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1132.50 (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 9.02(s, 1H), 8.76 (d, J = 8.9 Hz, 1H), 8.62 (t, J = 6.1 Hz, 1H), 8.55-8.49(m, 2H), 8.05 (d, J = 9.2 Hz, 1H), 7.91- 7.75 (m, 1H), 7.48-7.39 (m,5H), 7.29- 6.87 (m, 6H), 6.74 (s, 1H), 5.14 (dd, J = 10.9, 3.2 Hz, 1H),4.57 (d, J = 9.1 Hz, 1H), 4.48-4.28 (m, 4H), 4.30-4.13 (m, 2H),3.85-3.78 (m, 2H), 3.76- 3.55 (m, 4H), 3.50-3.38 (m, 5H), 3.28- 3.10 (m,2H), 3.11-2.76 (m, 3H), 2.70- 2.62 (m, 2H), 2.45 (s, 3H), 2.24 (d, J =12.0 Hz, 1H), 2.15-1.83 (m, 5H), 1.85-1.64 (m, 4H), 1.58-1.49 (m, 4H),1.24-1.19 (m, 1H), 1.11-1.02 (m, 5H), 0.98 (s, 9H). I91 

Tert-butyl N- [(2S,11S)-2-[[(2S)-4- carbamoyl-1-[4-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1063.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56(t, J = 6.1 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H),7.41 (q, J = 8.4 Hz, 4H), 7.25-7.22 (m, 1H), 7.13-7.02 (m, 5H), 6.95 (t,J = 7.4 Hz, 1H), 6.86-6.78 (m, 2H), 6.75- 6.72 (m, 1H), 5.13 (d, J = 3.5Hz, 1H), 5.03 (dd, J = 10.7, 2.8 Hz, 1H), 4.61-4.15 (m, 5H), 4.06-3.81(m, 4H), 3.71-3.62 (m, 2H), 3.44-3.38 (m, 1H), 3.18-2.95 (m, 2H),2.92-2.77 (m, 1H), 2.45 (s, 3H), 2.30-1.96 (m, 8H), 1.96- 1.44 (m, 8H),1.39 (s, 9H), 1.26 (q, J = 7.3 Hz, 2H), 0.93 (s, 9H) I92 

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1063.74 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.55(t, J = 6.1 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H),7.41 (q, J = 8.3 Hz, 4H), 7.23 (s, 1H), 7.17 (dd, J = 8.9, 7.4 Hz, 1H),7.12- 7.01 (m, 3H), 7.00-6.92 (m, 1H), 6.77- 6.71 (m, 4H), 5.12 (d, J =3.6 Hz, 1H), 5.04 (dd, J = 10.6, 2.7 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H),4.48-4.39 (m, 2H), 4.36 (s, 1H), 4.23 (dd, J = 15.9, 5.4 Hz, 1H),4.10-3.93 (m, 1H), 3.93- 3.85 (m, 3H), 3.72-3.61 (m, 3H), 3.45- 3.37 (m,2H), 3.12-2.99 (m, 3H), 2.86 (d, J = 16.6 Hz, 1H), 2.45 (s, 3H),2.31-2.23 (m, 1H), 2.13 (q, J = 7.6, 7.1 Hz, 2H), 2.06-2.01 (m, 4H),1.95- 1.61 (m, 1H), 1.61-1.44 (m, 4H), 1.39 (s, 9H), 1.31-1.23 (m, 3H),0.94 (s, 9H) I93 

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-[4-(2-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]ethyl) phenyl]propoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1063.33 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57(t, _(J) = 6.1 Hz, 1H), 7.99-7.83 (m, 2H), 7.41 (q, J = 8.3 Hz, 5H),7.24- 7.21 (m, 2H), 7.16-7.00 (m, 7H), 6.97- 6.92 (m, 1H), 6.71 (s, 1H),5.15 (d, J = 3.5 Hz, 1H), 5.06-4.98 (m, 1H), 4.55 (dd, J = 9.4, 2.1 Hz,1H), 4.50- 4.40 (m, 2H) 4.36 (s, 1H), 4.28-4.17 (m, 1H), 4.06-4.02 (m,2H), 3.82-3.77 (m, 1H), 3.70-3.65 (m, 2H), 3.51-3.34 (m, 2H), 3.33-3.25(m, 3H), 3.16-2.94 (m, 2H), 2.94-2.71 (m, 2H), 2.71- 2.55 (m, 2H), 2.45(s, 3H), 2.43-2.31 (m, 1H), 2.16-1.96 (m, 4H), 1.94-1.87 (m, 1H),1.78-1.70 (m, 3H), 1.66- 1.48 (m, 1H), 1.39 (s, 9H), 0.89 (s, 9H) I94 

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-([[4-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methyl](methyl) amino)butan-2-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1076.80 (400 MHz, CD₃OD) δ 8.89(s, 1H), 7.51-7.39 (m, 5H), 7.19 (d, J = 7.9 Hz, 1H), 7.15-7.00 (m, 5H),5.17-5.09 (m, 1H), 4.65 (d, J = 2.2 Hz, 1H), 4.62- 4.47 (m, 4H), 4.36(d, J = 15.4 Hz, 1 H), 4.30-4.16 (m, 1H), 4.07 (s, 1H), 3.91 (d, J =11.0 Hz, 1H), 3.84-3.80 (m, 1H), 3.59-3.37 (m, 3H), 3.24-3.03 (m, 4H),2.64-2.60 (m, 2H), 2.49 (s, 3H), 2.37-2.05 (m, 9H), 2.02-1.94 (m, 1H),1.69-1.62 (m, 7H), 1.47 (s, 9H), 1.05 (s, 9H) I95 

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1-carbamoyl- 4-[[4-(4-[[(2S)-1-[(2S,4S)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl] pyrrolidin-1-yl]-3,3- dimethyl-1-oxobutan-2-yl]carbamoyl]butyl)phenyl] methoxy]pentan-3-yl] carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1091.60 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.35 (d, J =7.6 Hz, 1H), 7.98 (d, J = 9.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.45(s, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.04 (td, J= 15.1, 14.6, 7.9 Hz, 2H), 5.13 (dd, J = 10.9, 3.4 Hz, 1H), 5.05-5.01(m, 1H), 4.57-4.43 (m, 3H), 4.37 (t, J = 4.5 Hz, 1H), 4.25 (d, J = 8.2Hz, 1H), 4.04-4.00 (m, 1H), 3.68 (dd, J = 10.5, 3.7 Hz, 1H), 3.62-3.53(m, 1H), 3.47 (dd, J = 16.6, 10.9 Hz, 1H), 3.17-3.13 (m, 2H), 3.01 (dd,J = 16.5, 3.4 Hz, 1H), 2.66-2.62 (m, 2H), 2.50 (s, 3H), 2.44-2.26 (m,2H), 2.25-2.15 (m, 2H), 2.07-2.03 (m, 7H), 1.95-1.86 (m, 1H), 1.74-1.61(m, 5H), 1.52 (d, J = 7.0 Hz, 3H), 1.48 (s, 9H), 1.20 (d, J = 6.3 Hz,3H), 1.05 (s, 9H) I96 

tert-butyl N- [(2S,11S)-2-[[(2S)-4- carbamoyl-1-[(9-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]nonyl) oxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1043.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56(t, J = 6.1 Hz, 1H), 7.83 (t, J = 8.6 Hz, 2H), 7.45-7.33 (m, 5H), 7.19(s, 1H), 7.14-6.99 (m, 3H), 6.99-6.90 (m, 1H), 6.69 (s, 1H), 5.12 (d, J= 3.6 Hz, 1H), 5.00 (dd, J = 12.0, 4.0 Hz, 1H), 4.55 (d, J = 9.4 Hz,1H), 4.48- 4.39 (m, 2H), 4.35 (s, 1H), 4.22 (dd, J = 15.8, 5.5 Hz, 1H),4.09-3.95 (m, 1H), 3.83-3.71 (m, 1H), 3.71-3.60 (m, 2H), 3.47-3.38 (m,1H), 3.31-3.30 (m, 4H), 3.29-3.24 (m, 2H), 3.15-2.94 (m, 2H), 2.87 (d, J= 16.5 Hz, 1H), 2.45 (s, 3H), 2.30-2.23 (m, 1H), 2.17-1.96 (m, 5H),1.94-1.87 (m, 1H), 1.79- 1.41 (m, 2H), 1.39 (s, 9H), 1.28-1.22 (m, 14H),0.94 (s, 9H) I97 

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[8-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]octyl) oxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1029.60 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56(t, J = 6.1 Hz, 1H), 7.95-7.77 (m, 2H), 7.45-7.36 (m, 5H), 7.20 (s, 1H),7.13-7.02 (m, 3H), 6.96 (d, J = 7.4 Hz, 1H), 6.74-6.65 (m, 1H),5.14-5.12 (m, 1H), 5.01 (dd, J = 10.7, 2.7 Hz, 1H), 4.55 (d, J = 9.4 Hz,1H), 4.49- 4.40 (m, 2H), 4.36-4.32 (m, 2H), 4.22 (dd, J = 15.8, 5.4 Hz,1H), 4.04 (t, J = 9.4 Hz, 1H), 3.79-2.75 (m, 2H), 3.70- 3.62 (m, 2H),3.51-3.41 (m, 1H), 3.30-3.24 (m, 2H), 3.15-2.96 (m, 2H), 2.92-2.79 (m,1H), 2.45 (s, 4H), 2.28- 2.24 (m, 1H), 2.15-1.95 (m, 8H), 1.92-1.89 (m,1H), 1.76-1.64 (m, 1H), 1.59-1.42 (m, 6H), 1.39 (s, 9H), 0.94 (s, 9H).I98 

tert-butyl ((3S,6S)-6- (((S)-5-amino-1-((8- (((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan- 2-yl)amino)-8-oxooctyl)oxy)-5- oxopentan-2- yl)carbamoyl)-4-oxo- 1,2,3,4,6,7-hexahydroazepino[3,2,1- hi]indol-3- yl)carbamate 1014.80 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 7.88-7.82 (m, 2H),7.48-7.35 (m, 4H), 7.22-7.17 (m, 1H), 7.09-7.01 (m, 3H), 6.96 (t, J =7.4 Hz, 1H), 6.69 (s, 1H), 5.12 (d, J = 3.5 Hz, 1H), 5.07-5.01 (m, 1H),4.55 (d, J = 9.4 Hz, 1H), 4.49-4.39 (m, 2H), 4.35 (s, 1H), 4.26-4.20 (m,1H), 4.04 (t, J = 9.3 Hz, 1H), 3.80-3.74 (m, 1H), 3.65 (t, J = 8.8 Hz,2H), 3.49- 3.40 (m, 1H), 3.28-3.25 (m, 2H), 3.11-2.96 (m, 2H), 2.91-2.82(m, 1H), 2.45 (s, 3H), 2.12-2.04 (m, 10H), 1.99- 1.85 (m, 1H), 1.68 (d,J = 7.0 Hz, 1H), 1.49-1.43 (m, 3H), 1.39 (s, 9H), 1.29-1.21 (m, 7H),0.94 (s, 9H) I99 

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-([[3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]methyl]carbamoyl) propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1076.61 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.56 (t, J = 6.1 Hz, 1H), 8.39 (t, J = 5.9 Hz, 1H), 8.20(d, J = 7.8 Hz, 1H), 7.90 (d, J = 9.4 Hz, 1H), 7.44-7.37 (m, 4H), 7.27(s, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.09-7.00 (m, 6H), 6.96 (t, J = 7.7Hz, 2H), 6.77 (s, 1H), 5.17-5.07 (m, 2H), 4.55 (d, J = 9.4 Hz, 1H),4.47- 4.39 (m, 2H), 4.35 (s, 1H), 4.27-4.18 (m, 4H), 4.10-3.99 (m, 1H),3.73- 3.61 (m, 2H), 3.41 (dd, J = 16.8, 10.9 Hz, 1H), 3.14-2.92 (m, 2H),2.45 (s, 3H), 2.37-2.22 (m, 1H), 2.19-1.97 (m, 7H), 1.94-1.87 (m, 2H),1.83-1.73 (m, 1H), 1.55-1.46 (m, 5H), 1.39 (s, 9H), 0.94 (s, 9H) I100

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[3-fluoro-4-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1109.75 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 13.7,9.3 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.23-7.15 (m, 2H), 7.12-6.99 (m, 5H), 6.95 (t, J = 7.4 Hz, 1H), 6.69 (s, 1H),5.12-5.02 (m, 2H), 4.92 (p, J = 7.2 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H),4.43 (q, J = 6.7, 5.4 Hz, 3H), 4.28 (s, 1H), 4.04 (t, J = 8.8 Hz, 1H),3.78 (s, 1H), 3.62-3.59 (m, 2H), 3.48-3.44 (m, 1H), 3.07 (s, 1H),3.02-2.98 (m, 1H), 2.86-2.82 (m, 1H), 2.60-2.56 (m, 2H), 2.46 (s, 3H),2.33-2.29 (m, 1H), 2.19- 2.07 (m, 1H), 2.05-2.01 (m, 6H), 1.84- 1.74 (m,1H), 1.57-1.50 (m, 6H), 1.40- 1.36 (m, 12H), 1.09 (d, J = 6.2 Hz, 3H),0.93 (s, 9H) I101

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1077.80 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.7 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.44 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.24 (s, 1H), 7.17(t, J = 8.1 Hz, 1H), 7.08 (dd, J = 21.9, 8.0 Hz, 3H), 6.96 (t, J = 7.4Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.73 (s, 3H), 5.13- 5.08 (m, 1H),5.03 (d, J = 10.7 Hz, 1H), 4.93 (q, J = 7.0 Hz, 1H), 4.52 (d, J = 9.2Hz, 1H), 4.42 (t, J = 7.8 Hz, 1H), 4.28 (s, 1H), 4.03 (d, J = 9.0 Hz,1H), 3.97 (s, 1H), 3.89 (s, 2H), 3.61 (s, 2H), 3.41 (dd, J = 16.9, 10.2Hz, 1H), 3.31 (s, 2H), 3.17-2.95 (m, 3H), 2.85 (d, J = 16.6 Hz, 1H),2.46 (s, 3H), 2.26-2.21 (m, 1H), 2.20-1.93 (m, 4H), 1.90-1.46 (m, 7H),1.39 (s, 9H), 1.37 (s, 3H), 1.31-1.22 (m, 3H), 0.93 (s, 9H) I102

9H-fluoren-9- ylmethyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[2-fluoro-4-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1217.47 (400 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.94-7.80 (m, 4H),7.74 (q, J = 8.0, 7.5 Hz, 3H), 7.45-7.39 (m, 5H), 7.35 (dd, J = 14.2,6.8 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.08-6.91 (m, 6H),6.68 (s, 1H), 5.15-5.01 (m, 2H), 4.62-4.08 (m, 11H), 3.83-3.60 (m, 3H),3.52- 3.36 (m, 2H), 3.20-2.97 (m, 2H), 2.84 (d, J = 16.5 Hz, 1H), 2.57(t, J = 7.1 Hz, 1H), 2.45 (s, 3H), 2.37-2.28 (m, 1H), 2.20-1.96 (m, 6H),1.95-1.69 m, 1H), 1.57-1.49 (m, 6H), 1.08 (d, J = 6.3 Hz, 3H), 0.94 (s,9H) I103

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-([4-[3-([[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]amino) propyl]phenyl]methoxy) pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1078.85 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H),7.46-7.37 (m, 3H), 7.26- 7.01 (m, 9H), 6.96 (dd, J = 8.3, 6.6 Hz, 1H),6.70-6.66 (m, 1H), 6.23-6.10 (m, 2H), 5.13 (s, 1H), 5.06 (dd, J = 10.7,2.8 Hz, 1H), 4.48-4.31 (m, 5H), 4.22 (dd, J = 15.9, 5.4 Hz, 1H), 4.04(t, J = 8.7 Hz, 1H), 3.78 (s, 1H), 3.69- 3.64 (m, 3H), 3.53-3.35 (m,4H), 3.15- 2.97 (m, 2H), 2.85 (d, J = 16.7 Hz, 1H), 2.56 (t, J = 7.4 Hz,2H), 2.07 (d, J = 11.8 Hz, 7H), 1.93-1.89 (m, 4.6 Hz, 1H), 1.79-1.75 (m,1H), 1.65 (t, J = 7.6 Hz, 2H), 1.57-1.53 (m, 2H), 1.39 (s, 9H), 1.08 (s,3H), 0.93 (s, 9H) I104

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[(8-[[(2,S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]oct-2- yn-1-yl)oxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1025.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.55(t, J = 6.1 Hz, 1H), 7.87 (dd, J = 9.0, 3.8 Hz, 2H), 7.45-7.36 (m, 5H),7.19 (s, 1H), 7.09-7.04 (m, 3H), 6.97- 6.93 (m, 1H), 6.70 (s, 1H), 5.12(d, J = 3.5 Hz, 1H), 5.02 (dd, J = 10.7, 2.7 Hz, 1H), 4.55 (d, J = 9.4Hz, 1H), 4.48-4.40 (m, 2H), 4.38-4.34 (m, 1H), 4.23 (dd, J = 15.9, 5.4Hz, 1H), 4.09 (d, J = 2.2 Hz, 2H), 4.03 (d, J = 8.4 Hz, 1H), 3.78-3.75(m, 1H), 3.72-3.59 (m, 2H), 3.44-3.42 (m, 1H), 3.15-2.93 (m, 2H),2.92-2.83 (m, 1H), 2.45 (s, 3H), 2.23-2.18 (m, 3H), 2.09-1.97 (m, 10H),1.92-1.89 (m, 1H), 1.81-1.66 (m, 1H), 1.63-1.42 (m, 2H), 1.41- 1.37 (m,12H), 0.94 (s, 9H). I105

tert-butyl N- [(2S,11S)-2-[[(2S)-4- carbamoyl-1-[[(2Z)-8-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]oct-2- en-1-yl]oxy]butan-2-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate [(M + Na)]⁺ = 1049.85 (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.86 (d, J = 9.0 Hz,2H), 7.41 (q, J = 8.3 Hz, 4H), 7.27-7.17 (m, 1H), 7.13-7.01 (m, 3H),6.95 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 15.7 Hz, 1H), 5.53-5.41 (m, 1H),5.13 (d, J = 3.5 Hz, 1H), 5.14-5.00 (m, 1H), 4.55 (d, J = 9.4 Hz, 1H),4.48- 4.39 (m, 2H), 4.36 (s, 1H), 4.22 (dd, J = 15.8, 5.6 Hz, 1H), 4.03(t, J = 7.7 Hz, 1H), 3.96 (d, J = 6.0 Hz, 2H), 3.78-3.70 (m, 1H),3.71-3.60 (m, 2 H), 3.46 (s, 2H), 3.28 (d, J = 5.6 Hz, 2H), 3.09-3.01(m, 2H), 2.91-2.82 (m, 1H), 2.45 (s, 3H), 2.27-2.24 (m, 1H), 2.12 (dd, J= 8.3, 6.2 Hz, 1H), 2.07- 1.95 (m, 6H), 1.99-1.91 (m, 1H), 1.70 (d, J =5.3 Hz, 1H), 1.57-1.44 (m, 4H), 1.39 (s, 9H), 1.30-1.21 (m, 4H), 0.94(s, 9H) I106

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1049.80 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.37(d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H),7.47-7.40 (m, 2H), 7.43-7.35 (m, 2H), 7.24 (s, 1H), 7.19 (t, J = 7.7 Hz,1H), 7.13-7.02 (m, 3H), 7.00-6.91 (m, 1H), 6.80-6.71 (m, 4H), 5.10 (s,1H), 5.04 (dd, J = 10.7, 2.8 Hz, 1H), 4.93 (p, J = 7.3 Hz, 1H), 4.55 (d,J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.04-4.00 (m,1H), 3.97-3.87 (m, 2H), 3.62 (d, J = 3.3 Hz, 2H), 3.42 (dd, J = 16.7,10.4 Hz, 1H), 3.04 (t, J = 9.3 Hz, 2H), 2.88-2.86 (m, 1H), 2.46 (s, 3H),2.30-2.26 (m, 1H), 2.22-2.11 (m, 2H), 2.10-1.97 (m, 1H), 1.86- 1.66 (m,2H), 1.42-1.37 (m, 18H), 1.34- 1.23 (m, 3H), 0.95 (s, 9H) I107

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-fluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1095.34 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.47-7.41 (m, 2H), 7.41-7.30 (m, 2H), 7.24 (s, 1H), 7.10 (d, J = 8.0 Hz,1H), 7.06-6.96 (m, 4H), 6.99-6.91 (m, 1H), 6.85-6.83 (m, 1H), 6.75 (s,1H), 5.10 (d, J = 3.6 Hz, 1H), 5.05-5.01 (m, 1H), 4.94-4.90 (m, 1H),4.52 (d, J = 9.3 Hz, 1H), 4.47-4.32 (m, 1H), 4.28 (s, 1H), 4.07-3.90 (m,1H), 3.61 (s, 2H), 3.48-3.44 (m, 1H), 3.12-2.96 (m, 1H), 2.92-2.82 (m,1H), 2.57 (t, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.26-2.22 (m, 1H),2.16-2.12 (m, 2H), 2.03-1.97 (m, 5H), 1.87-1.83 (m, 2H), 1.81-1.77 (m,1H), 1.74-1.66 (m, 1H), 1.56- 1.52 (m, 4H), 1.59-1.44 (m, 1H), 1.40-1.36 (m, 12H), 1.34-1.21 (m, 2H), 1.08-1.05 (m, 1H), 0.93 (s, 9H) I108

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- [[(4-methanesulfonylphenyl) methyl]carbamoyl] propyl]carbamoyl]-6-oxo-3-[2-[(1S,4S)-4- [[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1018.75 (300 MHz, DMSO-d₆) δ 11.06 (s,1H), 8.49 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.96-7.74 (m,2H), 7.50 (dd, J = 8.6, 2.9 Hz, 2H), 7.20 (s, 1H), 6.98 (dd, J = 8.7,4.4 Hz, 2H), 6.86- 6.72 (m, 2H), 6.52 (d, J = 6.9 Hz, 1H), 5.33 (dd, J =12.7, 5.3 Hz, 1H), 4.52-4.34 (m, 3H), 4.30-3.96 (m, 2H), 3.83-3.73 (m,2H), 3.31 (s, 3H), 3.18 (s, 3H), 3.01 (td, J = 6.7, 3.9 Hz, 3H),2.93-2.82 (m, 2H), 2.76-2.55 (m, 4H), 2.44-2.30 (m, 2H), 2.23-2.11 (m,2H), 2.05-1.88 (m, 4H), 1.86-1.57 (m, 5H), 1.44 (s, 9H), 1.48-1.30 (m,8H) I109

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- [[(4-isopropylphenyl)methyl] carbamoyl]propyl] carbamoyl]-6-oxo-3-[2-[(1S,4S)-4-[[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate  982.50 (300 MHz, DMSO-d₆) δ 11.09 (s,1H), 8.31 (t, J = 6.1 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.27-7.12 (m,5H), 7.00 (dd, J = 8.6, 5.5 Hz, 2H), 6.93-6.68 (m, 2H), 6.52 (d, J = 6.7Hz, 1H), 5.35 (dd, J = 12.7, 5.4 Hz, 1H), 4.55-3.96 (m, 6H), 3.88-3.68(m, 3H), 3.35- 3.32 (m, 7H), 3.23-3.08 (m, 1H), 3.01- 2.80 (m, 2H),2.80-2.55 (m, 6H), 2.47- 2.27 (m, 1H), 2.27-2.10 (m, 4H), 2.09 (s, 3H),1.86-1.58 (m, 1H), 1.58- 1.24 (m, 17H), 1.18 (dd, J = 6.9, 4.1 Hz, 6H)I110

tert-butyl N- (5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- [(naphthalen-1-ylmethyl)carbamoyl] propyl]carbamoyl]-6- oxo-3-[2-[(1S,4S)-4- [[1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate  990.75 (300 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.38 (t, J =5.7 Hz, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.10-7.99 (m, 1H), 7.99- 7.88 (m,1H), 7.84 (q, J = 4.0, 3.2 Hz, 1H), 7.60-7.49 (m, 2H), 7.49-7.40 (m,2H), 7.19 (s, 1H), 7.04-6.90 (m, 2H), 6.82 (t, J = 7.6 Hz, 1H), 6.70 (d,J = 15.0 Hz, 1H), 6.48 (d, J = 6.8 Hz, 1H), 5.33 (dd, J = 12.8, 5.4 Hz,1H), 4.74 (d, J = 5.6 Hz, 2H), 4.40 (q, J = 9.1 Hz, 2H), 4.25 (q, J =7.5 Hz, 1H), 4.21-3.91 (m, 2H), 3.86-3.65 (m, 2H), 3.52 (d, J = 10.6 Hz,1H), 3.31 (s, 3H), 3.22-2.80 (m, 4H), 2.76-2.54 (m, 4H), 2.47-2.21 (m,2H), 2.21-1.85 (m, 12H), 1.85-1.54 (m, 4H), 1.44 (s, 9H), 1.35 (m, 2H)I111

tert-butyl N-[(11S)-2- [[(2S)-4-carbamoyl-1- [4-chloro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1111.80 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.34(d, J = 7.7 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 9.3 Hz, 1H),7.41-7.39 (m, J = 8.3 Hz, 4H), 7.34- 7.18 (m, 2H), 7.10-7.00 (m, 3H),6.94 (d, J = 8.0, 6.7 Hz, 1H), 6.86 (d, J = 3.0 Hz, 1H), 6.78 (d, J =8.8, 2.9 Hz, 1H), 6.71 (s, 1H), 5.11-4.97 (m, 2H), 4.91 (d, J = 7.2 Hz,1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (d, J = 8.0 Hz, 1H), 4.30-4.24 (m,5H), 4.03 (s, 1H), 3.97-3.87 (m, 3H), 3.63--3.57 (m, 3H), 3.03-3.01 (m,3H), 2.82 (d, J = 16.7 Hz, 1H), 2.60 (m, 2H), 2.45 (s, 3H), 2.14-2.01(m, 1H), 1.86-1.63 (m, 2H), 1.52-1.50 (m, 3H), 1.38-1.35 (m, 11H),1.35-1.31 (m, 3H), 1.28-1.24 (m, 3H), 0.92 (s, 9H) I112

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-chloro-5-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1111.80 (300 MHz, DMSO-d₆) δ 9.03-8.97 (m, 2H),8.42-8.34 (m, 1H), 7.85-7.71 (m, 1H), 7.50-7.35 (m, 5H), 7.37-7.21 (m,2H), 7.08-6.96 (m, 4H), 6.84-6.72 (m, 2H), 4.44-4.42 (m, 1H), 4.30-4.28(m, 1H), 4.09-4.01 (m, 3H), 3.65- 3.59 (m, 3H), 3.42-3.25 (m, 10H),2.50-2.44 (m, 5H), 2.32-2.25 (m, 2H), 2.19-2.12 (m, 4H), 2.10-2.04 (m,2H), 1.59-1.51 (m, 5H), 1.39 (s, 9H), 1.32- 1.23 (m, 4H), 0.90 (s, 9H)I113

tert-butyl N-[(2S,11S)- 2-[[(3R)-1-carbamoyl- 5-[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1075.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.37(d, J = 7.8 Hz, 1H), 7.91-7.76 (m, 2H), 7.49-7.36 (m, 4H), 7.29-7.02 (m,5H), 7.02-6.92 (m, 4H), 6.69 (d, J = 6.9 Hz, 1H), 5.13-4.86 (m, 3H),4.53 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.33-4.24 (m, 1H),4.10-4.01 (m, 1H), 3.68-3.56 (m, 4H), 3.55- 3.41 (m, 1H), 3.12-2.93 (m,4H), 2.46 (s, 3H), 2.32-2.20 (m, 2H), 2.16-1.98 (m, 10H), 1.84-1.75 (m,2H), 1.75- 1.44 (m, 4H), 1.42-1.35 (m, 12H), 1.33- 1.19 (m, 2H), 0.94(s, 9H) I114

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[(1r,4r)-4-[2-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]ethyl] cyclohexanecarbonyl]- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1016.30 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.74 (d, J =8.5 Hz, 1H), 8.22-8.12 (m, 1H), 7.38-7.29 (m, 3H), 7.29 (td, J = 7.3,5.8, 3.5 Hz, 5H), 7.28-7.22 (m, 2H), 7.21 (s, 1H), 7.04-6.91 (m, 2H),6.86 (d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.34(dd, J = 12.7, 5.4 Hz, 1H), 4.47 (s, 1H), 4.43-4.29 (m, 2H), 4.08 (s,1H), 3.78 (dt, J = 12.4, 6.2 Hz, 1H), 3.71 (s, 2H), 3.33 (s, 3H), 3.22(s, 1H), 3.17-3.10 (m, 1H), 2.90 (s, 1H), 2.83 (s, 1H), 2.78-2.59 (m,4H), 2.22-2.05 (m, 2H), 2.05-1.55 (m, 11H), 1.53-1.46 (m, 1H), 1.41 (s,9H), 1.37-1.19 (m, 4H), 1.07-1.02 (m, 4H) I115

tert-butyl N-[(5S,8S,10aR)- 8-[[(1S)-3-carbamoyl- 1-(diphenylmethyl-carbamoyl)propyl] carbamoyl]-6-oxo- 3-[(1s,4s)- [4-[2-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl- 2-oxo-1,3-benzodiazol-5-yl]ethyl]cyclohexane- carbonyl]-octahydro- pyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate 1016.30 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.73(d, J = 8.5 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.38-7.22 (m, 11H), 7.20(s, 1H), 7.07-6.97 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 6.10(d, J = 8.4 Hz, 1H), 5.34 (dd, J = 12.8, 5.5 Hz, 1H), 4.45 (s, 1H), 4.36(dd, J = 19.1, 9.5 Hz, 2H), 4.09 (s, 1H), 3.72 (d, J = 14.0 Hz, 2H),3.32 (s, 3H), 3.21 (s, 1H), 3.12 (s, 1H), 2.96-2.84 (m, 2H), 2.74-2.63(m, 1H), 2.61 (s, 4H), 2.10 (d, J = 11.9 Hz, 4H), 2.04-1.97 (m, 1H),1.92 (s, 2H), 1.62-1.58 (m, 14H), 1.39 (s, 9H) I116

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-chloro-5-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1111.35 (300 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.37(d, J = 7.8 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H),7.47-7.36 (m, 5H), 7.27-7.20 (m, 1H), 7.05 (d, J = 7.5 Hz, 2H),7.00-6.91 (m, 1H), 6.87-6.78 (m, 2H), 6.76-6.69 (m, 2H), 5.10 (d, J =3.6 Hz, 1H), 5.07-4.99 (m, 1H), 4.98-4.87 (m 1H), 4.52 (d, J = 9.3 Hz,1H), 4.43 (t, J = 8.0 Hz, 1H), 4.32-4.26 (m, 1H), 4.04 (d, J = 8.6 Hz,1H), 3.99-3.86 (m, 3H), 3.67-3.55 (m, 2H), 3.45-3.38 (m, 1H), 3.13-3.97(m, 2H), 2.90- 2.80 (m, 1H), 2.46 (s, 3H), 2.33-2.21 (m, 1H), 2.19-1.95(m, 7H), 1.86-1.76 (m, 2H), 1.74-1.64 (m, 1H), 1.59-1.47 (m, 4H), 1.39(s, 9H), 1.38-1.36 (m, 2H), 1.32-1.22 (m, 4H), 0.94 (s, 9H) I117

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 2- methylphenoxy]butan- 2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1091.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.36(d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H),7.47-7.41 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.23 (s, 1H), 7.16-6.92 (m,7H), 6.78-6.68 (m, 3H), 5.14-5.00 (m, 2H), 4.96-4.89 (m, 1H), 4.55-4.49(m, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.07-4.00 (m, 2H),3.92-3.83 (m, 2H), 3.64-3.59 (m, 2H), 3.13-2.97 (m, 2H), 2.86 (dd, J =16.9, 2.8 Hz, 1H), 2.55-2.53 (m, 3H), 2.46 (s, 3H), 2.30-2.24 (m, 1H),2.19-2.09 (m, 2H), 2.04-1.98 (m, 1H), 1.92-1.67 (m, 2H), 1.63-1.43 (m,3H), 1.39 (s, 9H), 1.33-1.19 (m, 4H), 0.94 (s, 9H), 0.90- 0.80 (m, 7H)I118

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]cyclopropyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1090.85 (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.79(s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 9.4 Hz, 1H), 7.36-7.27(m, 4H), 7.25-7.13 (m, 2H), 7.08-7.04 (m, 3H), 6.95 (t, J = 7.4 Hz, 1H),6.75 (dd, J = 17.3, 7.2 Hz, 4H), 5.12 (d, J = 3.4 Hz, 1H), 5.06-5.02 (m,1H), 4.55 (d, J = 9.3 Hz, 1H), 4.41-4.37 (m, 2H), 4.05 (s, 1H), 3.98 (s,1H), 3.89 (t, J = 5.0 Hz, 1H), 3.65 (d, J = 3.5 Hz, 2H), 3.43-3.39 (m,1H), 3.04 (s, 2H), 2.86 (d, J = 17.0 Hz, 1H), 2.55 (s, 1H), 2.44 (s,3H), 2.31-2.27 (m, 1H), 2.17-2.09 (m, 2H), 2.04-2.00 (m, 1H), 1.93-1.86(m, 1H), 1.85 (s, 1H), 1.72-1.68 (m, 1H), 1.55 (s, 3H), 1.40 (s, 9H),1.34-1.23 (m, 5H), 1.21-1.12 (m, 1H), 0.94 (s, 9H), 0.91-0.80 (m, 6H)I119

tert-butyl N-[(11S)-2- [[(2S)-4-carbamoyl-1- [2-fluoro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1095.25 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.34(d, J = 7.8 Hz, 1H), 8.06 (s, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.40-7.35(m, 4H), 7.22 (s, 1H), 7.13-6.88 (m, 7H), 6.72 (s, 1H), 5.11-4.98 (m,1H), 4.97-4.86 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.42 (d, J = 8.0 Hz,1H), 4.28 (s, 2H), 4.01-3.97 (m, 5H), 3.60 (s, 2H), 3.03 (s, 2H),2.88-2.84 (m, 1H), 2.45 (s, 3H), 2.13-2.09 (m, 3H), 2.04- 2.00 (m, 3H),1.53-1.49 (m, 5H), 1.37- 1.31 (m, 13H), 1.24-1.20 (m, 6H), 0.92 (s, 9H)I120

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(5-[3-[1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5- yl]cyclobutyl]pentanoyl)-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5- yl]carbamate1016.40 (400 MHz, Chloroform-d) δ 9.34-8.49 (m, 1H), 7.82-7.77 (m, 1H),7.42-7.32 (m, 2H), 7.25-7.19 (m, 2H), 7.00- 6.66 (m, 5H), 6.41 (s, 1H),6.21 (d, J = 7.7 Hz, 2H), 5.90-5.48 (m, 3H), 5.26- 5.19 (m, 2H),4.90-4.12 (m, 7H), 4.05-3.88 (m, 3H), 3.45 (s, 3H), 3.41- 3.31 (m, 2H),3.20-3.04 (m, 3H), 2.98- 2.60 (m, 4H), 2.55-2.45 (m, 3H), 2.38- 1.79 (m,10H), 1.46 (s, 9H), 1.45- 1.19 (m, 6H) I121

tert-butyl N- [(2S,11S)-2-[[(1S)-3- carbamoyl-1-[[3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenyl]carbamoyl]propyl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1090.45 (300 MHzDMSO-d₆) δ 9.91 (s, 1H), 8.97 (s, 1H), 8.32 (dd, J = 15.7, 7.6 Hz, 2H),7.76 (d, J = 9.3 Hz, 1H), 7.45- 7.36 (m, 7H), 7.29 (s, 1H), 7.17 (t, J =8.1 Hz, 1H), 7.13-6.98 (m, 3H), 6.98-6.82 (m, 2H), 6.76 (s, 1H), 5.18-5.02 (m, 2H), 5.01-4.83 (m, 1H), 4.51 (d, J = 9.2 Hz, 1H), 4.42 (t, J =8.0 Hz, 1H), 4.33-4.26 (m, 2H), 4.05 (s, 1H), 3.60 (s, 2H), 3.51-3.35(m, 1H), 3.28 (s, 2H), 3.08-2.95 (m, 3H), 2.45 (s, 3H), 2.31-1.72 (m,9H), 1.59-1.45 (m, 3H), 1.38 (s, 11H), 1.36 (s, 2H), 1.32- 1.19 (m, 2H),0.92 (s, 9H) I122

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenoxy]pentan-3- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1077.45 (300 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.57(t, J = 6.0 Hz, 1H), 7.90 (dd, J = 25.3, 9.1 Hz, 2H), 7.49-7.34 (m, 5H),7.25-6.89 (m, 7H), 6.81-6.63 (m, 5H), 5.14 (d, J = 3.6 Hz, 1H),5.11-5.01 (m, 1H), 4.56 (d, J = 9.3 Hz, 1H), 4.50- 4.32 (m, 4H), 4.24(dd, J = 15.8, 5.4 Hz, 1H), 4.09-4.01 (m, 1H), 3.88-3.79 (m, 1H),3.72-3.63 (m, 2H), 3.11- 2.99 (m, 2H), 2.79 (d, J = 17.3 Hz, 1H), 2.46(s, 3H), 2.36-2.20 (m, 1H), 2.16-1.86 (m, 9H), 1.64-1.50 (m, 3H), 1.40(s, 9H), 1.31-1.26 (m, 3H), 1.19 (d, J = 6.1 Hz, 3H), 0.95 (s, 9H) I123

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1063.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 9.3 Hz, 1H),7.48-7.41 (m, 2H), 7.41-7.29 (m, 2H), 7.26-7.02 (m, 5H), 6.96 (dd, J =7.9, 7.0 Hz, 1H), 6.80-6.69 (m, 4H), 5.10 (d, J = 3.5 Hz, 1H), 5.06-5.02(m, 1H), 4.92 (p, J = 6.9 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J= 8.0 Hz, 1H), 4.28 (s, 1H), 4.07-3.95 (m, 1H), 3.95-3.83 (m, 2H),3.66-3.55 (m, 2H), 3.44-3.40 (m, 1H), 3.31 (s, 3H), 3.12- 2.97 (m, 1H),2.87-2.83 (m, 1H), 2.56- 2.52 (m, 2H), 2.46 (s, 3H), 2.31-2.27 (m, 1H),2.18-1.97 (m, 4H), 1.88- 1.64 (m, 3H), 1.55-1.51 (m, 4H), 1.39 (s, 9H),1.39-1.35 (m, 1H), 1.28-1.24 (m, 3H), 0.94 (s, 9H) I124

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 4- methylphenoxy]butan- 2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1091.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H),7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.24 (s, 1H), 7.10(d, J = 8.0 Hz, 1H), 7.03 (dd, J = 13.9, 7.9 Hz, 3H), 6.96 (dd, J = 8.0,6.9 Hz, 1H), 6.74 (s, 1H), 6.70-6.60 (m, 1H), 5.10- 5.08 (m, 1H),5.03-5.01 (m, 1H), 4.9-4.90 (m, 1H), 4.53-4.51 (m, 1H), 4.43-4.41 (m,1H), 4.28 (s, 1H), 4.07- 4.01 (m, 1H), 3.96-3.94 (m, 2H), 3.91- 3.79 (m,2H), 3.6-3.58 (m, 2H), 3.41- 3.38 (m, 1H), 3.16-2.97 (m, 2H), 2.85- 2.83(m, 1H), 2.45 (s, 3H), 2.28-2.26 (m, 1H), 2.18-2.16 (m, 3H), 2.12-2.10(m, 3H), 2.03-1.87 (m, 4H), 1.80- 1.78 (m, 2H), 1.73-1.62 (m, 2H), 1.62-1.43 (m, 4H), 1.38 (s, 9H), 1.37-1.35 (m, 2H), 1.32-1.30 (m, 1H),1.29-1.22 (m, 2H), 0.94 (s, 9H) I125

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 5- methylphenoxy]butan- 2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1091.50 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.44 (d, J = 8.3 Hz, 2H), 7.45-7.35 (m, 2H), 7.24 (s, 1H), 7.10 (d, J =8.0 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 6.96 (d, J = 8.1, 6.8 Hz, 1H),6.74 (s, 1H), 6.58 (s, 1H), 6.53 (d, J = 4.7 Hz, 2 H), 5.11 (d, J = 3.6Hz, 1H), 5.04 (d, J = 10.7, 2.7Hz, 1H), 4.94-4.90 (m, 1H), 4.52 (d, J =9.3 Hz, 1H), 4.43 (d, J = 8.0 Hz, 1H), 4.28 (m, 1H), 4.06- 4.02 (m, 1H),3.99-3.97 (m, 1H), 3.96- 3.81 (m, 2H), 3.63-3.59 (m, 2H), 3.43- 3.39 (m,1H), 2.88-2.84 (m, 1H), 2.24 (s, 3H), 2.16-2.02 (m, 4H), 1.82-1.78 (m,2H), 1.74-1.63 (m, 1H), 1.59-1.44 (m, 4H), 1.43-1.35 (m, 14H), 1.32-1.21 (m, 7H), 0.94 (s, 9H), 0.88-0.83 (m, 3H) I126

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 2- methylphenoxy]butan- 2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1091.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.36(d, J = 7.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 9.3 Hz, 1H),7.46-7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.23 (s, 1H), 7.11-7.02 (m,2H), 7.02-6.99 (m, 2H), 6.98-6.92 (m, 1H), 6.75-6.70 (m, 2H), 6.65 (d, J= 7.5, 1.4 Hz, 1H), 5.12-5.01 (m, 2H), 4.92 (s, 1H), 4.52 (d, J = 9.4Hz, 1H), 4.43 (s, 1H), 4.33-4.25 (m, 1H), 4.04- 4.00 (m, 2H), 3.93-3.89(m, 1H), 3.66-3.55 (m, 2H), 3.47-3.37 (m, 1H), 3.32-3.28 (m, 1H),3.06-2.97 (m, 1H), 2.90-2.81 (m, 1H), 2.46 (s, 3H), 2.33- 2.19 (m, 1H),2.15-2.11 (m, 1H), 2.10- 2.06 (m, 6H), 1.84-1.80 (m, 1H), 1.57-1.48 (m,3H), 1.42-1.36 (m, 12H), 1.29-1.24 (m, 4H), 0.93 (s, 9H), 0.89- 0.86 (m,3H), 0.85-0.84 (m, 2H) I127

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[4-fluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1095.50 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.47-.41 (m, 2H), 7.41-7.30 (m, 2H), 7.24 (s, 1H), 7.13-7.03 (m, 2H),7.07- 6.99 (m, 2H), 6.99-6.92 (m, 1H), 6.80 (dd, J = 6.2, 3.1 Hz, 1H),6.80-6.72 (m, 2H), 5.10 (d, J = 3.6 Hz, 1H), 5.05-5.02 (m, 1H),4.94-4.90 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H),4.28 (s, 1H), 4.03 (d, J = 8.5 Hz, 1H), 3.99-3.93 (m, 2H), 3.87 (t, J =5.2 Hz, 2H), 3.60 (s, 2H), 3.44-3.40 (m, 1H), 3.06-3.02 (m, 2H),2.87-2.83 (m, 1H), 2.56-2.52 (m, 2H), 2.46 (s, 3H), 2.30-2.20 (m, 1H),2.17- 1.96 (m, 5H), 1.81-1.77 (m, 1H), 1.71-1.67 (m, 1H), 1.57-1.44 (m,4H), 1.38 (s, 9H), 1.31-1.23 (m, 6H), 0.93 (s, 9H) I128

N-[(2S,11S)-2-[[(2S)- 4-carbamoyl-1-[3- fluoro-5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1095.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.48-7.37 (m, 4H), 7.24 (s, 1H), 7.08 (dd, J = 21.2, 7.8 Hz, 3H), 6.96(dd, J = 7.9, 6.9 Hz, 1H), 6.74 (s, 1H), 6.65-6.57 (m, 3H), 5.10 (d, J =3.6 Hz, 1H), 5.05-5.01 (m, 1H), 4.94-4.90 (m, 1H), 4.52 (d, J = 9.3 Hz,1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.07- 3.87 (m, 2H),3.66-3.55 (m, 2H), 3.44- 3.40 (m, 1H), 3.07 (s, 2H), 3.05-2.97 (m, 1H),2.85 (d, J = 16.5 Hz, 1H), 2.54 (s, 1H), 2.46 (s, 3H), 2.28-2.24 (m,1H), 2.14-2.10 (m, 2H), 2.04-2.00 (m, 4H), 1.85-1.75 (m, 1H), 1.71- 1.67(m, 1H), 1.55 (s, 3H), 1.51-1.47 (m, 1H), 1.40-1.36 (m, 12H), 1.27- 1.23(m, 5H), 0.93 (s, 9H) I129

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl)-3- methylphenyl]methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1105.65 (300 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 9.2 Hz, 2H), 7.41(q, J = 8.2 Hz, 4H), 7.23-6.88 (m, 9H), 6.69 (s, 1H), 5.14- 5.00 (m,2H), 4.92 (t, J = 7.2 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.46-4.33 (m,3H), 4.28 (s, 1H), 4.08-4.01 (m, 1H), 3.77 (s, 1H), 3.64-3.61 (m, 2H),3.47-3.41 (m, 1H), 3.10-2.95 (m, 2H), 2.84 (d, J = 16.7 Hz, 1H), 2.46(s, 3 H), 2.35-2.28 (m, 1H), 2.22 (s, 3H), 2.10-1.97 (m, 6H), 1.86-1.70(m, 2H), 1.61-1.46 (m, 3H), 1.39-1.34 (m, 16H), 1.07 (d, J = 6.2 Hz,3H), 0.94 (s, 9H) I130

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]pentan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1091.85 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.36(d, J = 7.8 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H),7.48-7.36 (m, 4H), 7.24-6.90 (m, 10 H), 6.78-6.63 (m, 4H), 5.15-5.04 (m,3H), 4.96-4.89 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.47-4.33 (m, 2H),4.33-4.25 (m, 1H), 4.14-3.98 (m, 2H), 3.86- 3.78 (m, 1H), 3.14-2.99 (m,5H), 2.46 (s, 3H), 2.17-1.72 (m, 9H), 1.70-1.45 (m, 5H), 1.40 (s, 9H),1.31-1.20 (m, 2H), 1.18 (d, J = 6.1 Hz, 3H), 0.94 (s, 9H) I131

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-([[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]methyl] carbamoyl)propyl] carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1104.65 (400 MHz, Methanol-d₄)δ 8.89 (s, 1 H), 7.48-7.41 (m, 4H), 7.20 (t, J = 7.5 Hz, 1H), 7.15-7.06(m, 6H), 7.04-6.99 (m, 1H),5.18 (dd, J = 10.8, 3.4 Hz, 1H), 5.02 (q, J =6.9 Hz, 1H), 4.66- 4.64 (m, 1H), 4.61-4.56 (m, 1H), 4.46- 4.40 (m, 2H),4.38 (d, J = 2.0 Hz, 2H), 4.25 (d, J = 8.6 Hz, 1H), 3.89 (d, J = 11.1Hz, 1H), 3.76 (dd, J = 11.0, 3.9 Hz, 1H), 3.54-3.46 (m, 1H), 3.18 (t, J= 6.3 Hz, 2H), 3.10 (dd, J = 16.8, 3.4 Hz, 1H), 2.58 (t, J = 7.5 Hz,2H), 2.50 (s, 3H), 2.32 (t, J = 7.5 Hz, 2H), 2.29-2.18 (m, 5H),2.01-1.93 (m, 2H), 1.65-1.53 (m, 4H), 1.52 (d, J = 7.0 Hz, 3H), 1.47 (s,9H), 1.31 (t, J = 7.7 Hz, 2H), 1.04 (s, 9H) I132

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1049.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57(t, J = 6.1 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 9.3 Hz, 1H),7.41 (q, J = 8.3 Hz, 4H), 7.24 (s, 1H), 7.17 (dd, J = 8.9, 7.5 Hz, 1H),7.11 (d, J = 8.1 Hz, 1H), 7.07-7.03 (m, 2H), 6.99-6.92 (m, 1H),6.79-6.69 (m, 5H), 5.13 (d, J = 3.5 Hz, 1H), 5.03 (dd, J = 10.7, 2.8 Hz,1H), 4.55 (d, J = 9.4 Hz, 1H), 4.48-4.39 (m, 2H), 4.35 (s, 1H), 4.22(dd, J = 15.8, 5.4 Hz, 1H), 4.07-3.93 (m, 1H), 3.92-3.85 (m, 2H),3.69-3.64 (m, 2H), 3.45-3.38 (m, 2H), 3.15-2.96 (m, 2H), 2.85 (d, J =16.5 Hz, 1H), 2.57-2.53 (m, 2H), 2.45 (s, 3H), 2.36-2.26 (m, 1H),2.20-1.98 (m, 6H), 1.95-1.76 (m, 1H), 1.76-1.63 (m, 1H), 1.59-1.47 (m,4H), 1.39 (s, 9H), 0.94 (s, 9H) I133

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-([[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- ([[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]methyl]carbamoyl) propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1090.65 (400 MHz, Methanol-d₄)δ 8.89 (s, 1H), 7.53-7.39 (m, 5H), 7.19 (t, J = 7.6 Hz, 1H), 7.12-7.03(m, 4H), 7.01 (t, J = 7.4 Hz, 1H), 5.17 (dd, J = 10.9, 3.4 Hz, 1H), 4.65(s, 1H), 4.63-4.55 (m, 2H), 4.54-4.50 (m, 2H), 4.45-4.38 (m, 2H), 4.36(d, J = 3.3 Hz, 2H), 4.25 (d, J = 8.9 Hz, 1H), 3.92 (d, J = 11.0 Hz,1H), 3.82-3.80 (m, 1H), 3.51-.378 (m, 1H), 3.25-3.05 (m, 2H), 2.58-2.53(m, 2H), 2.49 (s, 3H), 2.40-2.17 (m, 7H), 2.17-2.04 (m, 2H), 1.97-1.75(m, 1H), 1.63-1.58 (m, 4H), 1.47 (s, 9H), 1.39-1.24 (m, 2H), 1.04 (s,9H). I134

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-([4-[3-(1-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]cyclopropyl) propyl]phenyl] methoxy)pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1103.50 (400 MHz, Methanol-d₄)δ 8.90 (s, 1H), 7.53-7.40 (m, 4H), 7.23 (d, J = 7.9 Hz, 2H), 7.16 (d, J= 8.0 Hz, 2H), 7.07 (dd, J = 12.3, 7.2 Hz, 1H), 7.05- 6.99 (m, 1H), 6.94(d, J = 9.3 Hz, 1H), 5.12 (dd, J = 10.9, 3.4 Hz, 1H), 4.72 (d, J = 9.2Hz, 1H), 4.64-4.55 (m, 2H), 4.51 (s, 1H), 4.48 (d, J = 3.7 Hz, 2H), 4.35(d, J = 15.5 Hz, 1H), 4.25 (d, J = 8.7 Hz, 1H), 3.99 (s, 1H), 3.87 (d, J= 11.2 Hz, 1H), 3.81 (dd, J = 11.1, 3.8 Hz, 1H), 3.59-3.52 (m, 1H),3.50-3.41 (m, 1H), 3.13 (dd, J = 23.3, 17.8 Hz, 1H), 3.05-2.92 (m, 1H),2.66 (t, J = 7.2 Hz, 2H), 2.48 (s, 3H), 2.33- 2.16 (m, 4H), 2.09 (ddt, J= 13.8, 9.1, 4.5 Hz, 1H), 1.99 (s, 1H), 1.84-1.77 (m, 3H), 1.75-1.64 (m,1H), 1.52-1.49 (m, 3H), 1.48 (s, 9H), 1.31 (s, 1H), 1.21-1.09 (m, 4H),1.03 (s, 9H), 0.65 (d, J = 2.2 Hz, 2H) I135

9H-fluoren-9-ylmethyl N-[(2S,11S)-2-[[(3R)- 1-carbamoyl-5-[3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([[4-(3- methylthiophen-2-yl)phenyl]methyl] carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenyl]pentan-3- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1183.45 (400 MHz, DMSO-d₆) δ 8.98 (d, J = 0.9 Hz,1H), 8.57 (t, J = 6.1 Hz, 1H), 7.93-7.86 (m, 3H), 7.84 (s, 1H), 7.75 (q,J = 9.0, 8.3 Hz, 3H), 7.45-7.38 (m, 6H), 7.37-7.28 (m, 2H), 7.22 (d, J =18.8 Hz, 1H), 7.13 (q, J = 7.5, 7.0 Hz, 2H), 7.06 (d, J = 7.9 Hz, 1H),6.97 (d, J = 8.0 Hz, 4H), 6.71 (s, 1H), 5.06- 4.99 (m, 1H), 4.55 (d, J =9.3 Hz, 1H), 4.48-4.40 (m, 2H), 4.36 (s, 1H), 4.31- 4.09 (m, 5H),3.70-3.62 (m, 3H), 3.55-3.44 (m, 3H), 3.17-2.86 (m, 3H), 2.57 (d, J =25.3 Hz, 1H), 2.47 (d, J = 7.7 Hz, 2H), 2.45 (s, 3H), 2.33-2.21 (m, 1H),2.12 (d, J = 9.5 Hz, 3H), 2.05 (d, J = 6.7 Hz, 3H), 1.97-1.85 (m, 1H),1.64 (d, J = 17.5 Hz, 3H), 1.60- 1.44 (m, 5H), 1.32-1.21 (m, 2H), 0.94(s, 9H) I136

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[2-fluoro-4-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenyl]methoxy]pentan-3-yl]carbamoyl]-12- oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] trideca-4(13),5,7- trien-11-yl]carbamate 1109.65 Crude usednext step without further purification I137

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl)-2- methylphenyl]methoxy] pentan-3-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1105.45 (400 MHz, Methanol-d₄)δ 8.89 (s, 1H), 7.48-7.41 (m, 4H), 7.17 (d, J = 7.6 Hz, 1H), 7.08 (t, J= 7.4 Hz, 1H), 7.05-7.01 (m, 3H), 6.95 (d, J = 8.1 Hz, 1H), 5.12 (dd, J= 10.9, 3.4 Hz, 1H), 5.02 (q, J = 7.0 Hz, 1H), 4.65- 4.62 (m, 1H),4.61-4.53 (m, 2H), 4.49-4.43 (m, 2H), 4.28-4.21 (m, 1H), 4.05-3.95 (m,1H), 3.89 (d, J = 11.1 Hz, 1H), 3.76 (dd, J = 10.9, 4.0 Hz, 1H), 3.59(dd, J = 6.3, 4.6 Hz, 1H), 3.47 (dd, J = 16.7, 11.0 Hz, 1H), 3.18- 3.11(m, 2H), 3.02 (dd, J = 16.6, 3.4 Hz, 1H), 2.62-2.58 (m, 2H), 2.50 (s,3H), 2.33-2.30 (m, 4H), 2.28 (td, J = 5.3, 3.4 Hz, 3H), 2.25-2.16 (m,3H), 2.00-1.97 (m, 2H), 1.70-1.65 (m, 4H), 1.52 (d, J = 7.0 Hz, 3H),1.48 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H), 1.05 (s, 9H) I138

tert-butyl N-[(2S,11S)- 2-[[(3S,4R)-1- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[4-(4- methyl-1,3-thiazol-5-yl)phenoxy]carbamoyl] pyrrolidin-1-yl]-3,3- dimethyl-1-oxobutan- 2-yl]carbamoyl]butyl) phenyl]methoxy]pentan- 3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1079.53 (400 MHz, Methanol-d₄) δ 8.89 (s, 1H),7.41 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 7.7 Hz,2H), 7.15 (d, J = 7.8 Hz, 2H), 7.12- 6.99 (m, 3H), 5.13 (dd, J = 10.9,3.4 Hz, 1H), 4.65 (s, 1H), 4.55 (d, J = 10.2 Hz, 2H), 4.50 (d, J = 4.5Hz, 2H), 4.25 (dd, J = 8.3, 3.5 Hz, 1H), 4.03- 3.92 (m, 2H), 3.83 (dd, J= 11.0, 3.7 Hz, 1H), 3.60-3.54 (m, 1H), 3.51-3.43 (m, 1H), 3.16 (d, J =22.1 Hz, 2H), 3.01 (dd, J = 16.6, 3.4 Hz, 1H), 2.65 (s, 2H), 2.47 (s,3H), 2.39-2.24 (m, 5H), 2.24-2.14 (m, 3H), 2.02 (dd, J = 13.8, 7.8 Hz,1H), 1.67 (s, 4H), 1.48 (s, 9H), 1.31 (d, J = 5.5 Hz, 1H), 1.19 (d, J =6.3 Hz, 3H), 1.05 (s, 9H) I139

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 3-(4-[3-[1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]cyclobutyl]butanoyl)- 6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1002.40 (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.71 (d, J =8.5 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.41-7.18 (m, 11H), 7.11-7.07 (m,1H), 7.07-6.98 (m, 2H), 6.97-6.90 (m, 1H), 6.87 (d, J = 8.2 Hz, 1H),6.72 (d, J = 16.8 Hz, 1H), 6.49 (d, J = 6.3 Hz, 1H), 6.10 (d, J = 8.4Hz, 1H), 5.39-5.30 (m, 1H), 4.45- 4.35 (m, 2H), 4.12-3.98 (m, 1H),3.74-3.72 (m, 1H), 3.37-3.34 (m, 3H), 3.33-3.28 (m, 3 H), 3.17-2.99 (m,1H), 2.97-2.85 (m, 1H), 2.78-2.58 (m, 3H), 2.46-2.43 (m, 2H), 2.39-2.18(m, 3H), 2.17-1.87 (m, 6H), 1.85-1.42 (m, 8H), 1.42-1.33 (m, 10H). I140

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(3-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1090.55 (400 MHz, CD₃OD) δ 8.92-8.89 (m, 1H), 7.46-7.44 (m,4H), 7.04-6.92 (m, 2H), 6.86-6.81 (m, 1H), 5.03-5.01 (m, 1H), 4.67-4.64(m, 1H), 4.61-4.55 (m, 1H), 4.46-4.39 (m, 2H), 4.28-4.24 (m, 2H),4.07-4.05 (m, 1H), 4.01-3.95 (m, 1H), 3.90 (d, J = 10.8 Hz, 1H), 3.84-3.74 (m, 2H), 3.71-3.68 (m, 1H), 3.60-3.50 (m, 2H), 2.69-2.67 (m, 2H),2.45-4.42 (m, 2H), 2.36-4.32 (m, 3H), 2.26-2.17 (m, 6H), 2.12-2.06 (m,3H), 2.02-1.84 (m, 7H), 1.82-1.79 (m, 2H), 1.53 (d, J = 7.0 Hz, 3H),1.46 (s, 9H), 1.07 (s, 9H) I141

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-chloro-3-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1120.45 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.39 (d, J = 7.8Hz, 1H), 8.01 (dd, J = 8.4, 4.2 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H),7.48-7.30 (m, 4H), 7.24-7.15 (m, 2H), 7.01-6.97 (m, 1H), 6.91 (d, J =7.6 Hz, 1H), 6.75 (s, 1H), 6.68-6.58 (m, 1H), 5.11 (d, J = 3.5 Hz, 1H),4.93 (p, J = 7.1 Hz, 1H), 4.56-4.37 (m, 3H), 4.37-4.27 (m, 2H), 4.20 (d,J = 23.5 Hz, 2H), 4.07 (s, 1H), 4.03-3.09 (m, 1H), 3.93-3.87 (m, 1H),3.70-3.56 (m, 4H), 3.32 (s, 1H), 3.21-3.17 (m, 1H), 2.71-2.67 (m, 2H),2.47 (s, 3H), 2.36-2.27 (m, 1H), 2.25-2.11 (m, 3H), 2.08 (d, J = 1.9 Hz,3H), 2.07-1.95 (m, 2H), 1.91-1.74 (m, 2H), 1.74-1.62 (m, 2H), 1.57-1.43(m, 4H), 1.40 (s, 9H), 1.38 (s, 3H), 1.33-1.22 (m, 2H), 1.19-1.07 (m,1H), 0.94 (s, 9H) I142

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[2-[(1s,4s)-4-[[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1016.50 (400 MHz,DMSO-d₆) δ 11.09 (s,1H), 8.74 (d, J = 8.3 Hz, 1H), 8.29- 8.14 (m, 1H), 7.43-7.16 (m, 11H),7.06-6.92 (m, 2H), 6.89-6.68 (m, 2H), 6.47 (d, J = 6.7 Hz, 1H), 6.10 (d,J = 8.4 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.49-4.22 (m, 3H),4.14-3.97 (m, 6H), 3.83-3.75 (m, 1H), 3.32 (s, 3H), 3.21-3.05 (m, 1H),2.95-2.86 (m, 1H), 2.78-2.55 (m, 5H), 2.47-2.26 (m, 1H), 2.20-2.08 (m,5H), 2.04-1.87 (m, 1H), 1.87-1.51 (m, 4H), 1.46 (s, 9H), 1.43-1.30 (m,8H) I143

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-fluoro-3-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl)- 5- methylphenoxy]butan- 2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1081.50 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.35(d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H),7.40 (q, J = 8.4 Hz, 4H), 7.25 (s, 1H), 7.11-6.99 (m, 3H), 6.94 (dd, J =8.4, 6.3 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.72 (s, 1H), 6.64-6.56 (m,1H), 5.15- 4.98 (m, 2H), 4.91 (t, J = 7.2 Hz, 1H), 4.53 (d, J = 9.3 Hz,1H), 4.42 (t, J = 8.0 Hz, 1H), 4.32-4.25 (m, 1H), 4.09- 3.86 (m, 4H),3.65-3.58 (m, 2H), 3.49-3.37 (m, 2H), 3.17-2.93 (m, 3H), 2.85 (d, J =16.6 Hz, 1H), 2.59-2.51 (m, 1H), 2.45 (s, 3H), 2.22 (s, 3H), 2.20-2.09(m, 4H), 2.05-1.96 (m, 2H), 1.87-1.60 (m, 5H), 1.38 (s, 9H), 1.35 (s,3H), 0.94 (s, 9H) I144

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl)-5- methylphenoxy]butan-2-yl]carbamoyl]-6- oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1118.60 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.35 (d, J = 7.8Hz, 1H), 8.04-7.93 (m, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.40 (q, J = 8.4Hz, 4H), 7.17 (s, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.72 (s, 1H), 6.58 (dd,J = 10.9, 6.5 Hz, 2H), 5.08 (s, 1H), 4.91 (p, J = 7.2 Hz, 1H), 4.55-4.36 (m, 3H), 4.35-4.24 (m, 2H), 4.21-4.09 (m, 1H), 4.07-3.80 (m, 4H),3.72-3.51 (m, 4H), 3.37-3.26 (m, 4H), 2.45 (s, 3H), 2.34-2.25 (m, 1H),2.22 (s, 3H), 2.20-2.09 (m, 4H), 2.04-1.91 (m, 3H), 1.90-1.75 (m, 4H),1.74-1.56 (m, 4H), 1.55-1.45 (m, 4H), 1.37 (s, 9H), 1.35 (s, 3H), 0.92(s, 9H) I145

tert-butyl N-[(2S,11S)- 2-[[(3R)-1-carbamoyl- 6-[4-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenyl]hexan-3- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1075.60 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.39(d, J = 8.0 Hz, 1H), 7.91-7.67 (m, 2H), 7.49-7.29 (m, 4H), 7.13-7.00 (m,9H), 6.69 (s, 1H), 5.11 (d, J = 3.6 Hz, 1H), 5.03-4.81 (m, 2H),4.58-4.35 (m, 2H), 4.28 (s, 1H), 4.03 (s, 1H), 3.73-3.56 (m, 3H),3.53-3.37 (m, 3H), 3.15-2.78 (m, 1H), 2.46 (s, 3H), 2.36- 2.25 (m, 1H),2.20-1.91 (m, 6H), 1.86-1.72 (m, 1H), 1.67-1.29 (m, 17H), 1.39 (s, 9H),0.94 (s, 9H) I146

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[5-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) pyridin-2- yl]propyl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1048.60 (300 MHz, DMSO-d₆) δ 9.00 (s, 1H),8.66-8.59 (d, J = 7.9 Hz, 1H), 8.42- 8.33 (m, 2H), 7.81-7.79 (d, J = 9.3Hz, 1H), 7.59-7.56 (dd, J = 8.0, 2.4 Hz, 1H), 7.46-7.44 (d, J = 8.3 Hz,2H), 7.40-7.36 (d, J = 8.2 Hz, 2H), 7.26-7.18 (m, 2H), 7.14-7.12 (d, J =8.0 Hz, 1H), 7.06-7.02 (t, J = 7.5 Hz, 2H), 6.95-6.91 (t, J = 7.5 Hz,1H), 6.76 (s, 1H), 5.12-5.11 (d, J = 3.5 Hz, 1H), 5.08-5.06 (dd, J =10.8, 2.8 Hz, 1H), 4.96-4.89 (m, 1H), 4.72-4.66 (m, 1H), 4.53-4.48 (d, J= 9.3 Hz, 1H), 4.45-4.41 (t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.07-4.03(m, 1H), 3.62-3.61 (d, J = 3.9 Hz, 2H), 3.48-3.41 (m, 1H), 3.11-2.99 (m,2H), 2.77-2.69 (m, 1H), 2.71-2.65 (m, 2H), 2.47 (s, 3H), 2.29- 2.22 (m,1H), 2.18-2.03 (m, 3H), 2.06-1.98 (m, 1H), 1.98-1.85 (m, 1H), 1.83-1.77(m, 1H), 1.66-1.61 (m, 2H), 1.55-1.47 (m, 2H), 1.40-1.38 (m, 12H),1.32-1.25 (m, 2H), 0.94 (s, 9H) I147

tert-butyl N-[(2S)-1- [(2S)-2-[[(2S)-4- carbamoyl-1-[2-chloro-3-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenoxy]butan-2-yl]carbamoyl]pyrrolidin- 1-yl]-4-methyl-1- oxopentan-2- yl]carbamate1079.50 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H),7.84 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz,2H), 7.24-7.13 (m, 2H), 7.00-6.88 (m, 2H), 6.75 (s, 1H), 6.07 (s, 1H),4.93 (p, J = 7.2 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz,1H), 4.32-4.28 (m, 2H), 4.27-4.17 (m, 1H), 4.07-3.87 (m, 3H), 3.69-3.55(m, 3H), 3.51 (d, J = 6.3 Hz, 1H), 3.45-3.36 (m, 1H), 2.73- 2.65 (m,2H), 2.47 (s, 3H), 2.35-2.31 (m, 1H), 2.18-2.14 (m, 3H), 2.02-1.98 (m,2H), 1.91-1.75 (m, 3H), 1.73-1.62 (m, 1H), 1.61-1.42 (m, 4H), 1.41-1.37(m, 1H), 1.37 (s, 9H), 1.38-1.34 (m, 2H), 1.33-1.21 (m, 4H), 1.20-1.07(m, 1H), 0.94 (s, 9H), 0.88-0.84 (m, 6H) I148

tert-butyl N-[(2S)-1- [(2S)-2-[[(2S)-4- carbamoyl-1-[2-chloro-3-(3-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2-yl]carbamoyl]pyrrolidin- 1-yl]-4-methyl-1- oxopentan-2- yl]carbamate1065.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H),7.90 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.2 Hz,2H), 7.38 (d, J = 8.4 Hz, 2H), 7.22-7.15 (m, 2H), 6.98 (d, J = 8.4 Hz,1H), 6.93 (d, J = 8.2 Hz, 1H), 6.90-6.87 (d, J = 8.2 Hz, 1H), 6.72 (s,1H), 4.94-4.90 (m, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz,1H), 4.31-4.28 (m, 2H), 4.23- 4.18 (m, 1H), 4.09-4.02 (m, 1H), 3.99-3.96(m, 1H), 3.91-3.89 (m, 1H), 3.62 (d, J = 3.3 Hz, 3H), 3.54-3.46 (m, 3H),2.67 (t, J = 7.1 Hz, 2H), 2.46 (s, 3H), 2.33-2.29 (m, 1H), 2.24-2.12 (m,4H), 2.02-1.97 (m, 3H), 1.92-1.86 (m, 1H), 1.81-1.76 (m, 5H), 1.68-1.64(m, 2H), 1.38-1.34 (m, 12H), 0.95 (s, 9H), 0.88 (t, J = 6.4 Hz, 6H) I149

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-chloro-3-(3-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1106.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J = 7.8Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 7.44 (d, J= 8.3 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.24-7.17 (m, 2H), 6.99 (dd, J= 8.3, 3.2 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.75-6.71 (m, 1H), 6.68-6.58 (m, 1H), 6.06-6.01 (m, 2H), 4.92 (p, J = 7.2 Hz, 1H), 4.57-4.39 (m,2H), 4.37-4.25 (m, 2H), 4.25-4.14 (m, 1H), 4.11-3.96 (m, 2H), 3.91-3.88(m, 1H), 3.62 (d, J = 3.4 Hz, 3H), 3.48- 3.13 (m, 1H), 2.67-2.65 (m,2H), 2.46 (s, 3H), 2.31-2.29 (m, 1H), 2.18 (s, 3H), 2.08-2.05 (m, 3H),2.03-1.96 (m, 3H), 1.79-1.77 (m, 2H), 1.73-1.43 (m, 5H), 1.38 (s, 9H),1.25-1.22 (m, 2H), 1.18-1.01 (m, 2H), 0.95 (s, 9H), 0.85- 0.82 (m, 3H)I150

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[2-[(1s,4s)-4-[[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1016.45 (400 MHz, DMSO-d₆) δ 11.09 (s,1H), 8.76 (t, J = 8.0 Hz, 1H), 8.27- 8.19 (m, 1H), 7.37-7.20 (m, 10H),7.04-6.93 (m, 2H), 6.87-6.70 (m, 2H), 6.48 (d, J = 6.6 Hz, 1H), 6.10 (d,J = 8.4 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.54-4.19 (m, 3H),4.19- 3.88 (m, 1H), 3.83-3.75 (m, 2H), 3.37-3.35 (m, 5H), 3.32 (s, 3H),3.24- 3.02 (m, 1H), 2.98-2.82 (m, 1H), 2.77-2.55 (m, 4H), 2.46-2.25 (m,1H), 2.20-2.10 (m, 2H), 2.05-1.87 (m, 4H), 1.87-1.51 (m, 6H), 1.45-1.41(m, 13H), 1.38-1.29 (m, 3H) I151

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-chloro-3-(4-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]butyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1097.45 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.36(d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H),7.40 (q, J = 8.4 Hz, 4H), 7.19 (dd, J = 16.2, 8.3 Hz, 2H), 7.12-6.85 (m,6H), 6.73 (s, 1H), 6.01 (s, 2H), 5.74 (s, 1H), 5.03 (dd, J = 10.6, 2.7Hz, 1H), 4.90 (p, J = 7.2 Hz, 1H), 4.51 (d, J = 9.2 Hz, 1H), 4.42 (t, J= 8.0 Hz, 1H), 4.27 (s, 1H), 4.01 (s, 3H), 4.06-3.90 (m, 1H), 3.60 (d, J= 3.7 Hz, 2H), 3.42-3.38 (m, 1H), 3.05-3.01 (m, 2H), 2.95-2.91 (m, 1H),2.70-2.66 (m, 2H), 2.45 (s, 3H), 2.33-2.29 (m, 1H), 2.20- 2.08 (m, 3H),2.03 (d, J = 6.9 Hz, 3H), 1.86-1.66 (m, 1H), 1.55-1.51 (m, 4H),1.38-1.34 (m, 2H), 1.26-1.22 (m, 3H), 0.93 (s, 9H), 0.90-0.76 (m, 7H)I152

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[5-chloro-2-fluoro-3-(5-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]pentyl) phenoxy]butan-2-yl]carbamoyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1129.45 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.81(d, J = 9.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H),7.25 (s, 1H), 7.14-7.10 (m, 2H), 7.06-7.00 (m, 2H), 6.96 (d, J = 7.5 Hz,1H), 6.93-6.91 (m, 1H), 6.76 (s, 1H), 5.11 (d, J = 3.5 Hz, 1H),5.03-5.00 (m, 1H), 4.92 (t, J = 7.2 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H),4.42 (t, J = 8.0 Hz, 1H), 4.30-4.25 (m, 1H), 4.07-3.94 (m, 4H), 3.61 (d,J = 3.8 Hz, 2H), 3.43-3.38 (m, 2H), 3.05-3.01 (m, 2H), 2.85 (d, J = 16.0Hz, 1H), 2.57 (d, J = 7.3 Hz, 1H), 2.46 (s, 3H), 2.31-2.18 (m, 2H),2.17-2.10 (m, 3H), 2.06-1.96 (m, 3H), 1.83-1.78 (m, 2H), 1.70-1.68 (m,1H), 1.53-1.47 (m, 5H), 1.39 (s, 9H), 1.29-1.25 (m, 3H), 0.93 (s, 9H)I153

tert-butyl ((3S,6S)-6- ((5-amino-1-((2- chloro-3-(5-(((S)-1-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1- oxobutan-2-yl)amino)- 5-oxopentyl)phenyl)amino)- 1,5-dioxopentan- 2-yl)carbamoyl)-4-oxo-1,2,3,4,6,7- hexahydroazepino[3,2,1- hi]indol-3- yl)carbamate1110.40 (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.99 (s, 1H), 8.40 (t, J =8.4 Hz, 2H), 7.85 (dd, J = 9.3, 3.5 Hz, 1H), 7.62- 7.58 (m, 1H),7.48-7.41 (m, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 4.5 Hz, 1H),7.25 (td, J = 7.8, 5.8 Hz, 1H), 7.16-7.12 (m, 1H), 7.14-7.00 (m, 3H),6.99-6.95 (m, 1H), 6.82 (s, 1H), 5.14 (dt, J = 13.9, 3.5 Hz, 1H), 4.93(p, J = 7.0 Hz, 1H), 4.53 (dd, J = 9.3, 2.0 Hz, 1H), 4.44 (q, J = 9.5,8.0 Hz, 2H), 4.29 (s, 1H), 4.05 (t, J = 7.9 Hz, 1H), 3.62 (d, J = 4.0Hz, 2H), 3.48- 3.44 (m, 1H), 3.06-3.02 (m, 3H), 2.73-2.69 (m, 2H), 2.46(s, 3H), 2.36- 2.28 (m, 1H), 2.21-2.17 (m, 2H), 2.07-2.03 (m, 3H),1.95-1.74 (m, 2H), 1.58-1.49 (m, 5H), 1.42-1.35 (m, 12H), 1.32-1.19 (m,2H), 0.99-0.91 (m, 9H) I154

tert-butyl N-[(2S,11i)- 2-[[(1S)-3-carbamoyl- 1-[[2-chloro-3-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenyl]carbamoyl]propyl] carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1096.40 (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.99(s, 1H), 8.40 (t, J = 9.0 Hz, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.61 (dd, J= 23.2, 8.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H),7.33 (s, 1H), 7.27-7.23 (m, 1H), 7.15-7.02 (m, 4H), 6.99-6.95 (m, 1H),6.82 (s, 1H), 5.14 (dd, J = 14.8, 6.0 Hz, 2H), 4.93 (p, J = 7.2 Hz, 1H),4.55 (d, J = 9.6 Hz, 1H), 4.45 (s, 1H), 4.42 (d, J = 8.1 Hz, 1H),4.31-4.26 (m, 2H), 4.04 (d, J = 8.3 Hz, 1H), 3.62 (d, J = 3.1 Hz, 2H),3.51-3.40 (m, 1H), 3.05-3.01 (m, 3H), 2.70-2.66 (m, 2H), 2.46 (s, 3H),2.33-2.29 (m, 1H), 2.21-2.17 (m, 3H), 2.08-2.04 (m, 2H), 2.03-1.99 (m,1H), 1.90-1.86 (m, 1H), 1.81-1.77 (m, 2H), 1.42-1.35 (m, 12H), 1.27-1.22(m, 1H), 0.95 (s, 9H) I155

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[[3-(3-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenyl]carbamoyl]propyl] carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1062.35 (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.99(s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H), 7.86 (d, J= 9.2 Hz, 1H), 7.41 (dt, J = 15.3, 8.3 Hz, 6H), 7.32 (s, 1H), 7.20 (t, J= 7.8 Hz, 1H), 7.14-7.08 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 6.95 (t, J =7.5 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 5.13 (dd, J = 10.6,2.8 Hz, 1H), 4.92 (p, J = 7.1 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.43(t, J = 8.0 Hz, 1H), 4.29 (dd, J = 7.8, 5.1 Hz, 2H), 4.05-3.78 (m, 2H),3.62-3.45 (m, 3H), 3.03-2.95 (m, 3H), 2.54-2.51 (m, 1H), 2.46 (s, 3H),2.32-1.97 (m, 5H), 1.96-1.70 (m, 2H), 1.65-1.42 (m, 3H), 1.35 (s, 9H),1.05-1.01 (m, 6H), 0.95 (s, 9H) I156

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[[2-chloro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl]propyl] carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1124.55 (300 MHz, DMSO-d₆) δ 9.48-9.45 (m, 1H),9.00 (s, 1H), 8.40 (t, J = 8.0 Hz, 2H), 7.80 (d, J = 9.2 Hz, 1H),7.62-7.55 (m, 1H), 7.42 (q, J = 8.3 Hz, 4H), 7.33 (s, 1H), 7.28-7.22 (m,1H), 7.18-7.02 (m, 3H), 7.01-6.97 (m, 1H), 6.82 (s, 1H), 5.20-5.07 (m,2H), 4.98-4.88 (m, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.44 (t, J = 8.0 Hz,1H), 4.30 (s, 1H), 4.09-4.04 (m, 1H), 3.62 (s, 2H), 3.56-3.38 (m, 1H),3.34 (s, 2H), 3.05-2.99 (m, 3H), 2.69 (t, J = 7.7 Hz, 2H), 2.47 (s, 3H),2.35-1.96 (m, 10H), 1.96-1.74 (m, 1H), 1.61-1.48 (m, 3H), 1.41-1.28 (m,14H), 0.95 (s, 9H) I157

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[[2-fluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl]propyl] carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1108.55 (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 9.00(s, 1H), 8.38 (t, J = 7.1 Hz, 2H), 7.80 (d, J = 9.1 Hz, 1H), 7.72-7.67(m, 1H), 7.47-7.35 (m, 5H), 7.17-6.90 (m, 6H), 6.82 (s, 1H), 5.17-5.12(m, 2H), 5.03-4.84 (m, 1H), 4.58-4.39 (m, 3H), 4.30 (s, 1H), 4.09-4.04(m, 1H), 3.52-3.35 (m, 2H), 3.11-2.96 (m, 3H), 2.63-2.58 (m, 2H), 2.48(s, 3H), 2.35- 1.74 (m, 10H), 1.60-1.51 (m, 5H), 1.42-1.39 (m, 12H),1.35-1.18 (m, 2H), 0.95 (s, 9H) I158

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-fluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 4- methylphenoxy]butan- 2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1109.50 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H),7.44 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.27-7.22 (m, 1H),7.10 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.5 Hz, 2H), 6.99-6.92 (m, 1H),6.92-6.84 (m, 2H), 6.75 (s, 1H), 5.11 (d, J = 3.5 Hz, 1H), 5.03 (dd, J =10.8, 2.8 Hz, 1H), 4.92 (p, J = 7.2 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H),4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.09-4.00 (m, 1H), 3.97-3.85 (m,1H), 3.66-3.59 (m, 2H), 3.48-3.36 (m, 1H), 3.34 (s, 1H), 3.23- 2.95 (m,3H), 2.87 (d, J = 16.6 Hz, 1H), 2.56 (s, 2H), 2.46 (s, 3H), 2.30- 2.26(m, 1H), 2.21 (s, 3H), 2.18-1.97 (m, 4H), 1.89-1.76 (m, 1H), 1.76-1.64(m, 1H), 1.61-1.42 (m, 3H), 1.39 (s, 9H), 1.37 (s, 3H), 1.34-1.22 (m,5H), 1.17-1.05 (m, 1H), 0.94 (s, 9H) I159

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2,4-difluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]cabamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1113.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.44 (d, J = 8.3 Hz, 2H), 7.45-7.31 (m, 2H), 7.27-7.22 (m, 1H), 7.09 (t,J = 8.3 Hz, 1H), 7.04 (d, J = 7.2 Hz, 3H), 6.97-6.93 (m, 2H), 6.75 (s,1H), 5.10 (d, J = 3.6 Hz, 1H), 5.03 (dd, J = 10.7, 2.8 Hz, 1H),4.98-4.86 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H),4.31-4.21 (m, 1H), 4.11- 3.88 (m, 3H), 3.66-3.55 (m, 2H), 3.49-3.35 (m,1H), 3.12-2.97 (m, 1H), 2.90-2.82 (m, 1H), 2.64-2.56 (m, 2H), 2.46 (s,3H), 2.32-2.21 (m, 1H), 2.20- 1.96 (m, 6H), 1.88-1.75 (m, 1H), 1.73-1.63(m, 1H), 1.59-1.44 (m, 2H), 1.39 (s, 9H), 1.37 (s, 3H), 1.33-1.20 (m,6H), 1.19-1.05 (m, 1H), 0.93 (s, 9H) I160

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-chloro-3-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]-ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1083.45 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.33(d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H),7.40 (q, J = 8.3 Hz, 3H), 7.39 (s, 1H), 7.24-7.13 (m, 2H), 6.99 (dt, J =17.4, 7.3 Hz, 5H), 6.94-6.84 (m, 1H), 6.70 (s, 1H), 5.10-4.97 (m, 2H),4.91 (t, J = 7.3 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz,1H), 4.28 (s, 1H), 4.09-3.89 (m, 4H), 3.60 (d, J = 9.7 Hz, 2H), 3.40 (t,J = 14.2 Hz, 2H), 3.03 (s, 3H), 2.93 (d, J = 16.9 Hz, 1H), 2.67 (t, J =7.8 Hz, 2H), 2.45 (s, 3H), 2.32-2.10 (m, 3H), 2.07-1.95 (m, 2H),1.90-1.67 (m, 3H), 1.53-1.42 (m, 1H), 1.37 (d, J = 6.6 Hz, 12H), 1.23(s, 1H), 0.95 (s, 9H) I161

4-[3-[(2-[[(2S,11S)-11- [(tert- butoxycarbonyl)amino]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2-yl]formamido]- 4- carbamoylbutyl)(methyl) amino]-2-fluorophenyl]butyl N- [(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamate 1110.45 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.39 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H),7.47-7.41 (m, 3H), 7.38 (d, J = 8.2 Hz, 2H), 7.17 (s, 1H), 7.08 (s, 1H),7.02 (d, J = 6.6 Hz, 2H), 6.95- 6.91 (m, 2H), 6.77-6.73 (m, 3H), 5.11(d, J = 3.6 Hz, 1H), 4.92 (p, J = 12.5 Hz, 2H), 4.44 (t, J = 8.0 Hz,1H), 4.28 (s, 1H), 4.17 (d, J = 8.8 Hz, 1H), 4.02 (s, 2H), 3.97-3.93 (m,3H), 3.60 (s, 2H), 3.17-3.00 (m, 3H), 2.73 (s, 3H), 2.59 (s, 3H),2.59-2.55 (m, 2H), 2.46 (s, 3H), 2.06-2.02 (m, 2H), 1.81-1.77 (m, 1H),1.64-1.60 (m, 4H), 1.41-1.37 (m, 2H), 1.41-1.37 (m, 12H), 1.29- 1.25 (m,2H), 0.94 (s, 9H) I162

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-([[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]methyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M − H)]⁻ = 1019.60 (300 MHz, DMSO-d₆) δ 8.97 (s,1H), 8.37 (d, J = 7.8 Hz, 1H), 8.05 (dd, J = 15.2, 8.8 Hz, 2H),7.41-7.35 (q, J = 8.4 Hz, 4H), 7.23-6.66 (m, 10H), 5.15-4.86 (m, 3H),4.54-4.34 (m, 2H), 4.09-3.81 (m, 4H), 3.67-3.53 (m, 3H), 3.41 (d, J =13.6 Hz, 2H), 3.16-2.71 (m, 3H), 2.45 (s, 3H), 2.18-2.09 (m, 2H),1.99-1.97 (m, 2H), 1.91-1.61 (m, 4H), 1.40-1.35 (m, 13H), 0.91 (s, 9H)I163

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[[3-chloro-5-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl]propyl] carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M − 1)]⁻ = 1122.68 (300 MHz, DMSO-d₆) δ 10.12(d, J = 15.1 Hz, 1H), 9.00 (s, 1H), 8.38 (d, J = 7.7 Hz, 2H), 7.80 (d, J= 9.3 Hz, 1H), 7.63 (t, J = 1.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 3H), 7.39(d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 7.26 (s, 1H), 7.11 (s, 2H), 7.04 (d,J = 7.4 Hz, 1H), 7.01- 6.90 (m, 2H), 6.81 (s, 1H), 5.13 (d, J = 11.6 Hz,2H), 4.99-4.88 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz,1H), 4.29 (s, 2H), 4.06 (t, J = 8.4 Hz, 1H), 3.62 (s, 2H), 3.45 (t, J =13.6 Hz, 2H), 3.15-2.93 (m, 3H), 2.47 (s, 3H), 2.33-2.11 (m, 4H),2.01-1.73 (m, 5H), 1.66-1.45 (m, 5H), 1.44-1.31 (m, 12H), 1.30-1.22 (m,2H), 0.94 (s, 9H) I164

Tert-butyl N- [(2S,11S)-2-[[(1S)-3- carbamoyl-1-[[3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 5- methylphenyl]carbamoyl] propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1104.50 (400 MHz, DMSO-d₆) δ9.85 (s, 1H), 8.99 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 7.4Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.38 (d, J= 8.2 Hz, 2H), 7.36-7.30 (m, 1H), 7.26-7.21 (m, 2H), 7.10 (d, J = 7.5Hz, 2H), 7.04 (d, J = 7.9 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.79 (s,1H), 6.70 (s, 1H), 5.18-5.03 (m, 2H), 4.92 (p, J = 7.2 Hz, 1H), 4.52 (d,J = 9.3 Hz, 1H), 4.33-4.24 (m, 2H), 4.11-4.02 (m, 2H), 3.61 (d, J = 3.6Hz, 2H), 3.53- 3.40 (m, 2H), 3.15-2.93 (m, 3H), 2.52-2.43 (m, 5H),2.49-2.41 (m, 2H), 2.32-2.24 (m, 2H), 2.23 (s, 3H), 2.19- 1.74 (m, 6H),1.60-1.45 (m, 4H), 1.38 (s, 9H), 1.29-1.23 (m, 4H), 0.93 (s, 9H) I165

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[[3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 2- methylphenyl]carbamoyl] propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1104.50 (400 MHz, DMSO-d₆) δ9.39 (s, 1H), 8.99 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 7.5Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J= 8.3 Hz, 2H), 7.36-7.29 (m, 1H), 7.16-7.01 (m, 5H), 7.01-6.92 (m, 2H),6.86-6.77 (m, 1H), 5.21-5.06 (m, 2H), 4.96-4.90 (m, 1H), 4.53 (d, J =9.3 Hz, 1H), 4.47-4.23 (m, 6H), 4.13-3.99 (m, 1H), 3.80-3.77 (m, 2H),3.62 (d, J = 3.7 Hz, 2H), 3.53-3.39 (m, 1H), 3.38-3.26 (m, 4H),3.17-2.94 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.34-2.10 (m,2H), 2.04-1.98 (m, 3H), 1.95-1.68 (m, 1H), 1.68-1.44 (m, 3H), 1.40 (s,9H), 1.38 (s, 3H), 1.34-1.19 (m, 2H), 0.94 (s, 9H) I166

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[3-(2-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]ethyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1035.50 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.39(d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H),7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.25 (s, 1H),7.21-7.01 (m, 3H), 6.97 (q, J = 7.6 Hz, 2H), 6.83-6.70 (m, 3H), 5.76 (s,4H), 5.04 (ddd, J = 10.5, 6.5, 2.6 Hz, 2H), 4.93 (p, J = 7.1 Hz, 1H),4.54 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.29 (d, J = 3.9 Hz,1H), 4.12-3.94 (m, 2H), 3.94-3.86 (m, 2H), 3.62 (d, J = 3.4 Hz, 2H),3.46 (ddd, J = 32.8, 16.8, 11.1 Hz, 1H), 3.17-2.94 (m, 2H), 2.92-2.74(m, 2H), 2.46 (s, 3H), 2.23- 1.94 (m, 7H), 1.92-1.67 (m, 2H), 1.39 (s,9H), 0.91 (s, 9H) I167

tert-butyl N-(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-fluoro-3-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1067.45 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H),7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.27-7.23 (m, 1H),7.11 (d, J = 8.0 Hz, 1H), 7.06-7.00 (m, 4H), 6.98-6.92 (m, 1H),6.82-6.81 (m, 1H), 6.75 (s, 1H), 5.04 (d, J = 10.7 Hz, 1H), 4.92 (t, J =7.4 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.29(s, 1H), 4.05-3.97 (m, 4H), 3.63-3.61 (m, 2H), 3.43-3.39 (m, 1H),3.14-2.96 (m, 2H), 2.87 (d, J = 16.7 Hz, 1H), 2.58 (t, J = 7.8 Hz, 2H),2.46 (s, 3H), 2.37-2.25 (m, 1H), 2.24- 2.11 (m, 3H), 2.09-2.04 (m, 3H),2.07-1.94 (m, 4H), 1.93-1.63 (m, 5H), 1.39 (s, 9H), 0.95 (s, 9H) I168

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(5-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]pentyl)- 5-methylphenoxy]butan- 2-yl]carbamoyl]-6- oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1132.40 (300 MHz, DMSO-d₆) δ 8.97 (s,1H), 8.35 (d, J = 7.8 Hz, 1H), 8.01-7.93 (m, 1H), 7.82-7.74 (m, 1H),7.43 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.17 (s, 1H),6.83-6.52 (m, 4H), 5.08 (s, 1H), 4.97-4.83 (m, 1H), 4.51 (d, J = 9.3 Hz,2H), 4.42 (t, J = 8.0 Hz, 2H), 4.35-4.11 (m, 4H), 4.09-3.78 (m, 4H),3.74-3.51 (m, 5H), 3.48-3.10 (m, 6H), 2.45 (s, 3H), 2.22 (s, 3H),2.18-2.12 (m, 2H), 2.02-1.96 (m, 2H), 1.89-1.77 (m, 4H), 1.75-1.60 (m,4H), 1.57-1.43 (m, 5H), 1.38 (s, 9H), 1.35 (s, 3H), 0.92 (s, 9H) I169

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1104.50 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8Hz, 1H), 8.02 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.44 (d, J= 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.19 (s, 1H), 7.05-6.94 (m,2H), 6.82 (t, J = 6.5, 3.1 Hz, 1H), 6.75 (s, 1H), 6.67-6.56 (m, 1H),5.11 (d, J = 3.5 Hz, 1H), 4.93 (t, J = 7.1 Hz, 1H), 4.52 (d, J = 9.2 Hz,1H), 4.43 (t, J = 8.0 Hz, 1H), 4.35-4.27 (m, 2H), 4.25-4.12 (m, 2H),4.09-4.01 (m, 1H), 4.01-3.98 (m, 1H), 3.91-3.89 (m, 1H), 3.70-3.56 (m,4H), 3.36-3.30 (m, 2H), 3.23-3.14 (m, 1H), 2.60 (t, J = 6.7 Hz, 2H),2.46 (s, 3H), 2.32-2.28 (m, 1H), 2.25-2.13 (m, 2H), 2.08 (d, J = 3.7 Hz,3H), 2.06-1.92 (m, 2H), 1.85-1.78 (m, 2H), 1.70-1.66 (m, 2H), 1.53-1.49(m, 4H), 1.42-1.37 (m, 7H), 1.38-1.36 (s, 9H), 0.94 (s, 9H) I170

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[[3-fluoro-5-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]carbamoyl]propyl] carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1108.45 (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), 8.99(s, 1H), 8.38 (d, J = 7.6 Hz, 2H), 7.80 (d, J = 9.3 Hz, 1H), 7.49- 7.36(m, 5H), 7.34 (d, J = 10.0 Hz, 1H), 7.16-7.07 (m, 3H), 7.04 (d, J = 7.8Hz, 1H), 6.98-6.91 (m, 1H), 6.84- 6.77 (m, 1H), 6.75-6.70 (m, 1H),5.13-5.11 (m, 2H), 4.96-4.92 (m, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.43 (t,J = 8.1 Hz, 1H), 4.36 (d, J = 4.2 Hz, 2H), 4.28 (d, J = 5.8 Hz, 2H),4.12-3.99 (m, 1H), 3.79-3.78 (m, 2H), 3.61 (d, J = 3.5 Hz, 2H),3.53-3.39 (m, 1H), 3.35 (s, 5H), 3.18-2.91 (m, 2H), 2.58- 2.52 (m, 3H),2.46 (s, 3H), 2.31-2.09 (m, 2H), 2.07-1.75 (m, 2H), 1.60-1.48 (m, 4H),1.39 (s, 9H), 1.32-1.21 (m, 2H), 0.93 (s, 9H) I171

tert-butyl N-[(2S,11S)- 2-[(4-carbamoyl-1-[[2- fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenyl]amino]butan-2- yl)carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1094.50 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 7.96 (t, J = 8.7 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 14.6Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.08-7.00 (m, 3H), 7.01-6.91 (m, 1H),6.83 (t, J = 7.8 Hz, 1H), 6.72 (s, 1H), 6.62 (t, J = 8.4 Hz, 1H), 6.40(t, J = 7.1 Hz, 1H), 5.28 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 5.03-4.87(m, 2H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s,1H), 4.05 (s, 1H), 3.83 (s, 1H), 3.61 (s, 1H), 3.43-3.39 (m, 1H),3.33-3.29 (m, 1H), 3.10-3.06 (m, 4H), 3.06-2.97 (m, 1H), 2.84-2.80 (m,2H), 2.46 (s, 3H), 2.28-2.24 (m, 1H), 2.15- 2.11 (m, 1H), 2.07-2.03 (m,5H), 1.85-1.74 (m, 1H), 1.66-1.56 (m, 1H), 1.54-1.50 (m, 5H), 1.39 (s,9H), 1.41- 1.37 (m, 2H), 1.27-1.23 (m, 2H), 0.94 (s, 9H) I172

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-fluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl)- 5- methylphenoxy]butan- 2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1109.50 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.35(d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H),7.40 (q, J = 8.2 Hz, 4H), 7.22 (s, 1H), 7.11-6.99 (m, 3H), 6.99-6.88 (m,1H), 6.78 (dd, J = 7.8, 2.0 Hz, 1H), 6.72 (s, 1H), 6.65-6.56 (m, 1H),5.12-4.98 (m, 2H), 4.97-4.85 (m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.43 (q,J = 8.0, 6.7 Hz, 1H), 4.27 (s, 1H), 4.08-3.86 (m, 4H), 3.64-3.57 (m,2H), 3.48-3.25 (m, 5H), 3.17-2.96 (m, 2H), 2.91-2.79 (m, 1H), 2.59-2.51(m, 2H), 2.45 (s, 3H), 2.30- 2.23 (m, 1H), 2.21 (s, 3H), 2.18-2.09 (m,3H), 2.01-1.95 (m, 1H), 1.84-1.78 (m, 1H), 1.74-1.67 (m, 1H), 1.60-1.42(m, 5H), 1.38 (s, 9H), 1.35 (s, 3H), 0.92 (s, 9H) I173

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2,5-difluoro-3-(5-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1113.55 (400 MHz, CD3OD) δ 8.88 (s, 1H), 7.49-7.35(m, 4H), 7.12-7.06 (m, 2H), 7.04-6.97 (m, 1H), 6.82-6.74 (m, 1H),6.61-6.54 (m, 1H), 5.14 (dd, J = 11.0, 3.5 Hz, 1H), 5.06-4.99 (m, 1H),4.67- 4.62 (m, 1H), 4.58 (t, J = 8.2 Hz, 1H), 4.45 (br, 1H), 4.29-4.21(m, 2H), 4.10 (dd, J = 9.9, 4.6 Hz, 1H), 4.04-3.97 (m, 1H), 3.89 (d, J =11.1 Hz, 1H), 3.80-3.71 (m, 1H), 3.55-3.46 (m, 1H), 3.23-3.13 (m, 2H),3.06 (dd, J = 16.5, 3.5 Hz, 1H), 2.64 (t, J = 7.5 Hz, 2H), 2.50 (s, 3H),2.37 (t, J = 7.5 Hz, 2H), 2.33-2.16 (m, 5H), 2.11-1.80 (m, 2H),1.71-1.55 (m, 5H), 1.52 (d, J = 7.0 Hz, 3H), 1.48 (s, 9H), 1.44-1.34 (m,2H), 1.05 (s, 9H) I174

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[4-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]- 3,3-dimethyl-1- oxobutan-2-yl]carbamoyl]pentyl) pyridin-2- yl]propyl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate 1048.45 (300 MHz, DMSO-d₆) δ 8.97 (s, 1H),8.61-8.59 (d, J = 7.8 Hz, 1H), 8.38- 8.34 (t, J = 6.8 Hz, 2H), 7.79-7.76(d, J = 9.2 Hz, 1H), 7.47-7.31 (q, J = 8.4 Hz, 4H), 7.22 (s, 1H),7.16-6.98 (m, 5H), 6.96-6.85 (m, 1H), 6.74 (s, 1H), 5.10-5.06 (m, 2H),4.96-4.87 (p, J = 6.9 Hz, 1H), 4.68-4.61 (q, J = 7.3 Hz, 1H), 4.52-4.49(d, J = 9.3 Hz, 1H), 4.45-4.39 (t, J = 8.0 Hz, 1H), 4.27 (s, 1H),4.08-4.02 (d, J = 7.7 Hz, 1H), 3.61-3.60 (d, J = 3.4 Hz, 2H), 3.50-3.41(m, 1H), 3.04-3.02 (m, 2H), 2.94 (s, 3H), 2.80-2.74 (d, J = 2.4 Hz, 1H),2.68-2.64 (m, 2H), 2.45 (s, 3H), 2.24-2.16 (m, 1H), 2.17-2.08 (m, 2H),2.09-2.03 (d, J = 9.5 Hz, 2H), 1.92-1.73 (m, 3H), 1.66-1.60 (m, 2H),1.55-1.45 (m, 2H), 1.38 (s, 9H), 1.30-1.25 (m, 3H), 0.92 (s, 9H) I175

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[4-[(1r,4s)-4-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]cyclohexyl]butanoyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1030.55 (300 MHz, CD3OD) δ 8.73 (s, 1H),7.33-7.26 (m, 10H), 7.08-7.06 (m 1H), 7.04-6.97 (m, 2H), 6.17-6.11 (m,1H), 5.33-5.30 (m, 1H), 4.61 (d, J = 9.9 Hz, 1H), 4.45-4.41 (m, 2H),4.25- 4.23 (m, 1H), 3.82-3.77 (m, 2H), 3.45-3.40 (m, 3H), 2.95-2.75 (m,3H), 2.64-2.59 (m, 3H), 2.35 (d, J = 8.3 Hz, 2H), 2.20-2.14 (m, 4H),1.96 (d, J = 9.7 Hz, 3H), 1.78-1.61 (m, 15H), 1.58-1.50 (m, 2H), 1.45(s, 9H) I176

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[3-[(1s,4s)-4-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]cyclohexyl]propanoyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1016.50 (300 MHz, DMSO-d₆) δ 11.09 (s,1H), 8.73 (d, J = 8.4 Hz, 1H), 8.19 (t, J = 6.4 Hz, 1H), 7.41-7.20 (m,10H), 7.09-6.85 (m, 3H), 6.73 (d, J = 12.2 Hz, 1H), 6.49 (d, J = 6.8 Hz,1H), 6.11 (d, J = 8.3 Hz, 1H), 5.34 (dd, J = 12.8, 5.4 Hz, 1H),4.53-4.24 (m, 3H), 4.15- 4.11 (m, 2H), 3.74-3.71 (m, 3H), 3.27- 3.06 (m,4H), 2.89-2.58 (m, 4H), 2.15-2.13 (m, 4H), 1.88-1.62 (m, 12H), 1.69-1.45(m, 4H), 1.40 (s, 9H), 1.07-1.05 (m, 4H) I177

tert-butyl N- (5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[4-[(1s,4r)-4-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]cyclohexyl]butanoyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1030.55 (300 MHz, CD3OD) δ 7.39-7.21 (m,10H), 7.05-6.97 (m, 3H), 6.14 (d, J = 6.3 Hz, 1H), 5.33-5.30 (m, 1H),4.62 (d, J = 11.9 Hz, 1H), 4.46-4.40 (m, 2H), 4.25-4.23 (m, 1H),3.81-3.77 (m, 2H), 3.41 (m, 3H), 3.10-2.86 (m, 2H), 2.81 (d, J = 4.9 Hz,1H), 2.78-2.76 (m, 1H), 2.55-2.51 (m, 2H), 2.39-2.36 (m, 2H), 2.28-2.10(m, 4H), 1.99-1.90 (m, 8H), 1.78-1.74 (m, 3H), 1.57-1.53 (m, 2H), 1.46(s, 9H), 1.45-1.05 (m, 7H) I178

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(5-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]pentyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1118.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38 (d, J = 7.8Hz, 1H), 8.02 (t, J = 7.4 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.44 (d, J= 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.19 (s, 1H), 7.08-6.96 (m,2H), 6.86-6.78 (m, 1H), 6.74 (s, 1H), 6.67-6.56 (m, 1H), 5.10 (d, J =3.5 Hz, 1H), 4.92 (q, J = 7.5 Hz, 1H), 4.55-4.39 (m, 2H), 4.37-4.26 (m,2H), 4.18 (d, J = 9.8 Hz, 1H), 4.04 (s, 1H), 3.98 (t, J = 7.2 Hz, 1H),3.92-3.88 (m, 1H), 3.66 (d, J = 12.6 Hz, 1H), 3.61 (s, 3H), 3.52-3.35(m, 1H), 3.24-3.13 (m, 1H), 2.58-2.54 (m, 3H), 2.46 (s, 3H), 2.32-2.18(m, 2H), 2.17-2.05 (m, 4H), 2.03-1.97 (m, 2H), 1.92-1.76 (m, 3H),1.74-1.65 (m, 2H), 1.52-1.48 (m, 4H), 1.39 (s, 9H), 1.37 (s, 3H),1.37-1.23 (m, 6H), 0.93 (s, 9H) I179

tert-butyl N-[(2S)-1- [(2S)-2-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(4-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenoxy]butan-2-yl]carbamoyl]pyrrolidin- 1-yl]-4-methyl-1- oxopentan-2- yl]carbamate1063.55 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H),7.83 (t, J = 8.5 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.3 Hz,2H), 7.16 (s, 1H), 7.06-6.88 (m, 3H), 6.82 (s, 1H), 6.73 (s, 1H), 5.10(s, 1H), 4.92 (t, J = 7.3 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J= 8.0 Hz, 1H), 4.29 (s, 2H), 4.21 (s, 1H), 3.98 (d, J = 13.6 Hz, 2H),3.94-3.90 (m, 1H), 3.66-3.55 (m, 3H), 3.53-3.49 (m, 1H), 2.59-2.56 (m,3H), 2.46 (s, 3H), 2.34-2.26 (m, 1H), 2.16-2.12 (m, 3H), 2.03-1.98 (m,3H), 1.92-1.72 (m, 2H), 1.71-1.63 (m, 1H), 1.57-1.43 (m, 5H), 1.37 (s,9H), 1.33- 1.23 (m, 3H), 0.93 (s, 9H), 0.91-0.82 (m, 9H) I180

tert-butyl N- (5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- (diphenyl-methylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[3- [(1r,4r)-4-[1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]cyclohexyl]propanoyl]- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1016.50 (300 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.73 (d, J =8.4 Hz, 1H), 8.21 (d, J = 7.3 Hz, 1H), 7.31 (q, J = 7.7, 6.8 Hz, 11H),7.14-6.88 (m, 3H), 6.75 (s, 1H), 6.47 (d, J = 6.6 Hz, 1H), 6.11 (d, J =8.4 Hz, 1H), 5.77 (d, J = 1.0 Hz, 1H), 5.40-5.25 (m, 1H), 4.41 (dd, J =23.7, 14.0 Hz, 3H), 4.15-4.13 (m, 1H), 3.76 (d, J = 14.4 Hz, 1H), 2.90-2.84 (m, 4H), 2.79-2.58 (m, 5H), 2.24-1.86 (m, 11H), 1.85-1.53 (m, 13H),1.39 (s, 9H) I181

tert-butyl N-[(2S)-1- [(2S)-2-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(5-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin- 1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]pentyl) phenoxy]butan-2-yl]carbamoyl]pyrrolidin- 1-yl]-4-methyl-1- oxopentan-2- yl]carbamate1077.15 (300 MHz, CD3OD) δ 8.88 (s, 1H), 7.47-7.40 (m, 4H), 7.00-6.89(m, 2H), 6.84-6.77 (m, 1H), 5.03-5.00 (m, 1H), 4.64-4.54 (m, 2H),4.44-4.41 (m, 3H), 4.25-4.21 (m, 1H), 4.07-4.02 (m, 1H), 3.98-3.96 (m,1H), 3.91-3.80 (m, 2H), 3.77-3.76 (m, 1H), 3.64-3.62 (m, 1H), 2.65-2.62(m, 2H), 2.49 (s, 3H), 2.40- 2.36 (m, 2H), 2.32-2.25 (m, 2H), 2.22-2.14(m, 2H), 2.10-2.05 (m, 1H), 1.98-1.95 (m, 3H), 1.66-1.61 (m, 5H),1.55-1.51 (m, 4H), 1.44 (s, 9H), 1.41- 1.29 (m, 4H), 1.04 (s, 9H),0.99-0.93 (m, 6H) I182

tert-butyl N-[(2S,11S)- 2-[[(1S)-3-carbamoyl- 1-[[3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin- 1-yl]- 3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl]carbamoyl]propyl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- trien-11-yl]carbamate 1076.60. (300 MHz DMSO-d₆) δ9.94 (s, 1H), 9.00 (s, 1H), 8.35 (dd, J = 16.5, 7.4 Hz, 2H), 7.81 (d, J= 9.2 Hz, 1H), 7.50-7.35 (m, 6H), 7.32 (s, 1H), 7.20 (s, 1H), 7.16-7.00(m, 2H), 6.93 (dd, J = 25.3, 7.5 Hz, 1H), 6.79 (s, 1H), 5.16-5.10 (m,2H), 4.96-4.91 (m, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.43 (t, J = 7.9 Hz,1H), 4.33-4.28 (m, 2H), 4.10- 4.04 (m, 1H), 3.62 (s, 2H), 3.09-2.98 (m,3H), 2.47 (s, 3H), 2.33-2.27 (m, 1H), 2.20-1.73 (m, 10H), 1.58-1.48 (m,6H), 1.41-1.36 (m, 14H), 0.95 (s, 9H) I183

4-[3-[(2S)-2- [[(2S,11S)-11-[(tert- butoxycarbonyl)amino]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2-yl]formamido]- 4-carbamoylbutoxy]- 2-fluorophenyl]butylN-[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4- (4-methyl-1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]- 3,3-dimethyl-1-oxobutan-2- yl]carbamate 1097.80 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.39(d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.4 Hz, 1H), 7.48-7.41 (m, 2H), 7.45-7.33 (m, 2H), 7.24 (s, 1H), 7.13-6.90 (m, 7H), 6.86-6.82 (m, 1H), 6.74(s, 1H), 5.11 (s, 1H), 5.05-5.01 (m, 1H), 4.93-4.89 (m, 1H), 4.44 (t, J= 8.0 Hz, 1H), 4.28 (s, 1H), 4.17 (d, J = 9.0 Hz, 1H), 4.06-3.98 (m,2H), 3.98-3.94 (m, 5H), 3.62-3.58 (m, 2H), 2.86 (d, J = 16.5 Hz, 1H),2.62 (s, 3H), 2.46 (s, 3H), 2.16-2.12 (m, 2H), 2.07-1.98 (m, 3H),1.61-1.57 (m, 5H), 1.41-1.34 (m, 12H), 1.33-1.24 (m, 1H), 1.27-1.23 (m,2H), 0.94 (s, 9H) I188

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- ([[4-(propane-2-sulfonyl)phenyl]methyl] carbamoyl)propyl] carbamoyl]-6-oxo-3-[2-[(1s,4s)-4-[[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1046.45 (400 MHz, DMSO-d₆) δ 11.09 (s,1H), 8.53 (t, J = 6.0 Hz, 1H), 8.28 (t, J = 7.4 Hz, 1H), 7.81-7.76 (m,2H), 7.53 (t, J = 6.6 Hz, 2H), 7.24 (s, 1H), 7.03-6.94 (m, 2H),6.87-6.69 (m, 2H), 6.54 (d, J = 6.8 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz,1H), 4.47-4.35 (m, 5H), 4.25-4.20 (m, 1H), 3.84-3.72 (m, 2H), 3.43-3.36(m, 2H), 3.32 (s, 3H), 3.25- 2.99 (m, 1H), 2.95-2.86 (m, 1H), 2.77-2.55(m, 6H), 2.45-2.25 (m, 1H), 2.23-2.10 (m, 4H), 2.04-1.92 (m, 5H),1.87-1.53 (m, 6H), 1.45-1.32 (m, 12H), 1.16-1.13 (m, 8H) I189

tert-butyl N-[(2S,11S)- 2-[[(2S)-4-carbamoyl- 1-[2-chloro-3-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-([1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]cyclopropyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-11-yl]carbamate [(M − 1)]⁻ = 1093.50 (300 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.86-8.79 (m, 1H), 8.16-8.00 (m, 2H), 7.37-7.28 (m, 3H), 7.25 (d, J= 7.9 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H),7.09-7.01 (m, 3H), 7.00-6.89 (m, 3H), 6.79-6.73 (m, 1H), 5.09-5.01 (m,1H), 4.59 (d, J = 9.3 Hz, 1H), 4.45-4.38 (m, 2H), 4.08-3.94 (m, 4H),3.69-3.64 (m, 2H), 3.13-2.90 (m, 4H), 2.76-2.68 (m, 2H), 2.45 (s, 3H),2.38-2.31 (m, 1H), 2.26-2.12 (m, 3H), 2.09-1.97 (m, 3H), 1.94-1.72 (m,6H), 1.40 (s, 9H), 1.27-1.14 (m, 4H), 0.96 (s, 9H) I190

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-chloro-3-(3-[[(2S)-1- [(2S,4R)-4-hydroxy-2- ([1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]cyclopropyl] carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1118.60 (300 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.85-8.81 (m,1H), 8.06-7.99 (m, 2H), 7.39-7.28 (m, 4H), 7.26-7.20 (m, 2H), 7.13-6.97(m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 6.69-6.55 (m, 1H), 4.58(d, J = 9.2 Hz, 1H), 4.41- 4.35 (m, 4H), 4.23-4.09 (m, 1H), 4.12-3.98(m, 2H), 3.94-3.90 (m, 1H), 3.68-3.61 (m, 4H), 3.36-3.15 (m, 1H),3.09-3.02 (m, 1H), 2.76-2.64 (m, 2H), 2.46 (s, 3H), 2.37-2.32 (m, 1H),2.25- 2.18 (m, 3H), 2.12-2.07 (m, 3H), 2.03-1.59 (m, 13H), 1.39 (s, 9H),1.27-1.12 (m, 4H), 0.96 (s, 9H) I191

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- [[(4-methanesulfonylphenyl) methyl]carbamoyl] propyl]carbamoyl]-3-(4-[2-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]ethyl]cyclohexane- carbonyl)-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1018.35 (300 MHz, DMSO-d₆) δ 11.10 (s,1H), 8.53 (d, J = 6.5 Hz, 1H), 8.27 (d, J = 7.5 Hz, 1H), 7.87 (d, J =8.3 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 7.23 (s, 1H), 7.01 (d, J = 8.9Hz, 2H), 6.87 (d, J = 7.9 Hz, 1H), 6.77 (s, 1H), 6.57 (d, J = 6.9 Hz,1H), 5.35 (dd, J = 12.8, 5.4 Hz, 1H), 4.48 (s, 1H), 4.40 (d, J = 5.2 Hz,3H), 4.29-3.99 (m, 2H), 3.71 (d, J = 14.7 Hz, 2H), 3.20 (s, 3H),3.00-2.72 (m, 1H), 2.70-2.58 (m, 3H), 2.14-2.10 (m, 4H), 2.09-2.05 (m,6H), 2.04-2.01 (m, 7H), 1.84-1.79 (m, 5H), 1.66-1.61 (m, 2H), 1.49-1.47(m, 2H), 1.40 (s, 9H), 1.19-1.15 (m, 3H) I192

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- [[(4-methanesulfonylphenyl) methyl]carbamoyl] propyl]carbamoyl]-6-oxo-3-[2-[(1r,4r)-4- [[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1018.40 (300 MHz, DMSO-d6) δ 11.11 (s,1H), 8.58-8.48 (m, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.87 (dd, J = 8.2, 2.9Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.23 (s, 1H), 7.01 (d, J = 7.9 Hz,2H), 6.83 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 10.9 Hz, 1H), 6.62 (d, J =7.1 Hz, 1H), 5.36 (dd, J = 12.7, 5.3 Hz, 1H), 4.49-4.33 (m, 4H),4.27-4.18 (m, 1H), 4.14-4.07 (m, 1H), 3.68 (d, J = 12.7 Hz, 2H), 3.34(s, 3H), 3.20 (s, 3H), 3.16-2.82 (m, 3H), 2.81-2.58 (m, 3H), 2.50- 2.47(m, 1H), 2.35-2.26 (m, 1H), 2.24-2.11 (m, 4H), 2.07-1.87 (m, 4H),1.86-1.59 (m, 10H), 1.40 (s, 9H), 1.04-0.87 (m, 4H) I193

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- [[(4-methanesulfonylphenyl) methyl]carbamoyl] propyl]carbamoyl]-3-[7-[1-(2,6- dioxopiperidin-3-yl)- 3-methyl-2-oxo-1,3- benzodiazol-5-yl]heptanoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate  992.25 (300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.56-8.47 (m,1H), 8.25 (d, J = 7.6 Hz, 1H), 7.87 (dd, J = 8.3, 1.6 Hz, 2H), 7.52 (d,J = 8.1 Hz, 2H), 7.23 (s, 1H), 7.05-6.98 (m, 2H), 6.87 (d, J = 7.7 Hz,1H), 6.78 (s, 1H), 6.59 (d, J = 6.9 Hz, 1H), 5.35 (dd, J = 12.7, 5.4 Hz,1H), 4.54-4.34 (m, 4H), 4.29-4.07 (m, 2H), 3.70 (d, J = 13.8 Hz, 2H),3.34 (s, 3H), 3.19 (s, 3H), 3.15-3.07 (m, 1H), 2.99-2.84 (m, 1H),2.80-2.55 (m, 4H), 2.49-2.26 (m, 2H), 2.23-2.11 (m, 3H), 2.07-1.91 (m,3H), 1.90-1.72 (m, 4H), 1.72-1.47 (m, 6H), 1.40 (s, 9H), 1.37-1.28 (m,4H) I194

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-chloro-5-fluoro-3-(3- [[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] carbamoyl]pyrrolidin- 1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1123.90 (300 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.38 (d, J = 7.7Hz, 2H), 8.01-7.99 (m, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.48-7.36 (m, 4H),7.20-7.00 (m, 2H), 6.78-6.59 (m, 3H), 5.11 (d, J = 3.4 Hz, 1H),4.97-4.89 (m, 1H), 4.54-4.44 (m, 2H), 4.32-4.28 (m, 2H), 4.12-4.10 (m,1H), 4.05-4.02 (m, 1H), 3.93-3.75 (m, 4H), 2.76-2.60 (m, 4H), 2.47 (s,3H), 2.34-2.10 (m, 9H), 2.09-1.60 (m, 13H), 1.39 (s, 9H), 1.36 (d, J =7.0 Hz, 3H), 0.96 (s, 9H) I195

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(3-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin- 1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl)- 5-methylphenoxy]butan- 2-yl]carbamoyl]-6- oxo- octahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 1104.55 (400 MHz, DMSO-d₆) δ 8.99 (s,1H), 8.38 (d, J = 7.8 Hz, 1H), 8.05-7.97 (m, 1H), 7.87 (d, J = 9.2 Hz,1H), 7.44 (d, J = 8.3 Hz, 2H), 7.44-7.35 (m, 2H), 7.19 (s, 1H), 6.82 (d,J = 7.7 Hz, 1H), 6.75 (s, 1H), 6.67-6.57 (m, 2H), 5.10 (d, J = 3.0 Hz,1H), 4.92 (p, J = 7.4 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.49 (s, 1H),4.43 (t, J = 8.0 Hz, 1H), 4.37-4.26 (m, 2H), 4.25-4.14 (m, 1H),4.06-4.00 (m, 1H), 3.97 (d, J = 10.4 Hz, 1H), 3.92-3.84 (m, 1H),3.71-3.59 (m, 4H), 3.18 (t, J = 12.6 Hz, 1H), 2.88-2.80 (m, 1H), 2.46(s, 3H), 2.34- 2.10 (m, 7H), 2.08 (d, J = 3.0 Hz, 3H), 2.00 (d, J = 8.6Hz, 1H), 1.92-1.77 (m, 4H), 1.75-1.59 (m, 4H), 1.57-1.45 (m, 1H), 1.39(s, 9H), 1.37 (s, 3H), 1.32-1.22 (m, 4H), 0.95 (s, 9H) I196

tert-butyl N- [(5S,8S,10aR)-3- acetyl-8-[[(2S)-4- carbamoyl-1-[2,5-difluoro-3-(3-[[(2S)-1- [(2S,4R)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin- 1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl) phenoxy]butan-2-yl]carbamoyl]-6-oxo- octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamate 1108.56 (300 MHz, DMSO-d₆) δ 9.00 (d, J = 1.3 Hz, 1H), 8.39(d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.54-7.41(m, 4H), 7.39-7.37 (m, 1H), 7.20-7.18 (m, 1H), 7.00 (s, 1H), 6.72 (d, J= 28.1 Hz, 1H), 6.09 (s, 1H), 4.94 (t, J = 7.1 Hz, 1H), 4.54 (d, J = 9.3Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.32-4.29 (m, 1H), 4.21-4.19 (m, 1H),4.05-4.01 (m, 2H), 3.94-3.91 (m, 1H), 3.65-3.61 (m, 4H), 2.93-2.91 (m,1H), 2.60-2.56 (m, 2H), 2.49 (s, 3H), 2.35- 1.96 (m, 12H), 1.88-1.65 (m,9H), 1.39-1.36 (m, 12H), 0.96 (s, 9H) I197

tert-butyl ((5S,8S,10aR)-3- acetyl-8-(((S)-5- amino-1-(2-chloro-3-(4-(((S)-1-((2S,4R)-4- hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl)pyrrolidin- 1-yl)- 3,3-dimethyl-1-oxobutan-2-yl)amino)- 4-oxobutyl)-5- methylphenoxy)-5- oxopentan-2-yl)carbamoyl)-6- oxodecahydropyrrolo [1,2-a][1,5]diazocin-5-yl)carbamate 1120.45 (300 MHz, DMSO-d₆) δ 9.00 (d, J = 1.2 Hz, 1H), 8.39(d, J = 7.7 Hz, 1H), 8.01 (dd, J = 8.7, 3.2 Hz, 1H), 7.89 (d, J = 9.1Hz, 1H), 7.50-7.35 (m, 4H), 7.21 (s, 1H), 6.85 (s, 1H), 6.76-6.72 (m,2H), 6.69-6.52 (m, 1H), 5.12 (s, 1H), 4.99-4.89 (m, 1H), 4.57-4.51 (m,1H), 4.44 (t, J = 8.1 Hz, 1H), 4.38- 4.25 (m, 1H), 4.12-3.82 (m, 2H),3.73-3.54 (m, 4H), 3.49-3.17 (m, 12H), 2.63 (t, J = 7.7 Hz, 2H), 2.47(s, 3H), 2.34-2.16 (m, 6H), 2.10 (d, J = 1.3 Hz, 6H), 1.93-1.55 (m, 4H),1.41- 1.38 (d, J = 6.7 Hz, 12H), 0.97 (s, 9H) I198

tert-butyl N- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl-1- [[(4-methanesulfonylphenyl) methyl]carbamoyl] propyl]carbamoyl]-6-oxo-3-[(1s,4s)-4-[2-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]ethyl]cyclohexane- carbonyl]-octahydropyrrolo[1,2- a][1,5]diazocin-5- yl]carbamate 1018.45 (300 MHz,Chloroform-d) δ 9.36 (d, J = 15.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 3H),7.42 (d, J = 8.1 Hz, 3H), 7.01 (d, J = 8.1 Hz, 1H), 6.92-6.74 (m, 3H),6.53 (s, 1H), 6.04-5.90 (m, 1H), 5.88- 5.67 (m, 1H), 5.29-5.15 (m, 1H),5.08-4.99 (m, 1H), 4.59-4.40 (m, 4H), 4.12-3.85 (m, 2H), 3.39 (s, 3H),3.03 (s, 3H), 2.90-2.69 (m, 2H), 2.68-2.55 (m, 3H), 2.54-2.36 (m, 2H),2.34-2.09 (m, 6H), 1.91-1.80 (m, 2H), 1.79-1.62 (m, 7H), 1.44 (s, 9H)

Tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-7-[14-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]butoxy]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (Intermediate1184)

Tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-7-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]butoxy]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate. To a solutionof3-[5-(4-bromobutyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione(234 mg, 0.59 mmol) in DMF (6 mL) was added NaH (48 mg, 1.19 mmol, 60 wt% in mineral oil) at 0° C. The mixture was stirred for 15 min followedby the addition of3-[5-(4-bromobutyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione(234 mg, 0.59 mmol) and the mixture was stirred for 16 h at ambienttemperature. The reaction was quenched by the addition of sat. NH₄Cl(aq.) (4 mL) at 0° C. The resulting mixture was filtered. The filteredcake was washed with DMF (3×1 mL). The filtrate was concentrated underreduced pressure. The residue was purified by reverse phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 120 g; Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN;Gradient: 35%-60% B in 25 min; Flow rate: 50 mL/min; Detector: UV220/254 nm; desired fractions were collected at 50% B and concentratedunder reduced pressure to afford tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-7-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]butoxy]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (90 mg, 15%) asa yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.78-8.72 (m,1H), 8.35-8.11 (m, 1H), 7.42-7.15 (m, 11H), 7.11-6.84 (m, 5H), 6.83-6.53(m, 2H), 6.10 (dd, J=8.5, 3.7 Hz, 1H), 5.35 (dd, J=12.5, 5.0 Hz, 1H),5.21-4.92 (m, 1H), 4.38-4.32 (m, 1H), 4.14-4.05 (m, 3H), 3.78 (q, J=6.3Hz, 1H), 3.22 (s, 3H), 3.06-2.58 (m, 6H), 2.20-1.87 (m, 6H), 1.82-1.74(m, 6H), 1.39 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=969.40.

The intermediates in Table 51 were prepared according to the procedureto prepare Intermediate 1184

TABLE 51 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMR I185

Tert-butyl N- [(2S,11S)-2-[[(1S)- 3-carbamoyl-1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 7-([6-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]hexyl]oxy)-12- oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 4(13),5,7-trien-11- yl]carbamate 997.45 (300 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 8.30-8.24 (m, 2H),7.36-7.28 (m, 11H), 7.11-6.84 (m, 4H), 6.81- 6.50 (m, 2H), 6.10 (dd, J =8.5, 3.7Hz, 1H), 5.35 (dd, J = 12.5, 5.0 Hz, 1H), 5.21- 4.92 (m, 2H),4.38-4.32 (m, 1H), 4.14-4.05 (m, 4H), 3.78 (q, J = 6.3 Hz, 2H), 3.22 (s,3H), 3.06-2.58 (m, 6H), 2.20-1.87 (m, 6H), 1.82-1.74 (m,6H), 1.39 (s,9H), 1.28-1.21 (m, 2H)

(3R,5S)-1-[(2S)-2-(6-[3-[(2S)-2-[[(2S,11S)-11-[(tert-butoxycarbonyl)amino]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-2-yl]formamido]-4-carbamoylbutoxy]-2-fluorophenyl]hexanamido)-3,3-dimethylbutanoyl]-5-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-3-ylacetate (Intermediate 1186)

(3R,5S)-1-[(2S)-2-(6-[3-[(2S)-2-[[(2S,11S)-11-[(tert-butoxycarbonyl)amino]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-2-yl]formamido]-4-carbamoylbutoxy]-2-fluorophenyl]hexanamido)-3,3-dimethylbutanoyl]-5-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-3-ylacetate. To a stirred solution of tert-butylN-[(2S,11S)-2-[[(2S)-4-carbamoyl-1-[2-fluoro-3-(5-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]pentyl)phenoxy]butan-2-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (800 mg, 0.73mmol), TEA (185 mg, 1.83 mmol) and DMAP (8.92 mg, 0.073 mmol) in DMA (1mL) was added acetyl chloride (287 mg, 3.65 mmol) in DMA (1 mL) dropwiseat 0° C. under nitrogen atmosphere. After stirring for 2 h at roomtemperature, the mixture was purified by reverse phase flashchromatography with the following conditions: column, Spherical C18Column, 20-40 um, 330 g; Mobile Phase A: Water (plus 10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Gradient: 30% to 50% B in 20 min; Detector: UV254/220 nm. Desired fractions were collected at 43% B, concentratedunder reduced pressure and lyophilized to afford(3R,5S)-1-[(2S)-2-(6-[3-[(2S)-2-[[(2S,11S)-11-[(tert-butoxycarbonyl)amino]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-2-yl]formamido]-4-carbamoylbutoxy]-2-fluorophenyl]hexanamido)-3,3-dimethylbutanoyl]-5-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-3-ylacetate (755 mg, 91%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.99(s, 1H), 8.41 (d, J=7.8 Hz, 1H), 8.08 (d, J=7.4 Hz, 1H), 7.82 (d, J=8.7Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.24 (s, 1H),7.13-7.02 (m, 3H), 7.02-6.91 (m, 3H), 6.84-6.80 (m, 1H), 6.74 (s, 1H),5.19 (s, 1H), 5.06-5.02 (m, 1H), 4.91 (q, J=7.1 Hz, 1H), 4.47 (t, J=8.4Hz, 1H), 4.36 (d, J=8.7 Hz, 1H), 4.00-3.96 (m, 5H), 3.76-3.72 (m, 1H),3.44-3.40 (m, 1H), 3.08 (s, 1H), 3.01 (d, J=17.2 Hz, 1H), 2.89-2.85 (m,1H), 2.59-2.55 (m, 2H), 2.46 (s, 3H), 2.25-2.21 (m, 2H), 2.12 (dd,J=14.8, 7.7 Hz, 3H), 2.00 (s, 3H), 1.84 (s, 1H), 1.71 (s, 1H), 1.53-1.49(m, 5H), 1.39 (s, 9H), 1.34-1.23 (m, 6H), 1.15-1.11 (m, 1H), 0.95 (s,9H); LC/MS (ESI, m/z): [(M+1)]⁺=1137.50.

Tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-[(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl)methyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (Intermediate1187)

Step 1:3-[3-methyl-2-oxo-5-[(4-oxocyclohexyl)methyl]-1,3-benzodiazol-1-yl]piperidine-2,6-dione.To a stirred solution of3-(5-[1,4-dioxaspiro[4.5]decan-8-ylmethyl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione(1 g, 2.42 mmol) in DCM (40 mL) was added TFA (4 mL, 53.8 mmol). Theresulting mixture was stirred for 2 h at ambient temperature undernitrogen atmosphere. The resulting mixture was concentrated underreduced pressure. The crude product was purified by reverse phase flashchromatography with the following conditions (Column: Spherical C18Column, 20-40 um, 120 g; Mobile Phase A: Water (plus 0.1% TFA), MobilePhase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 25 min;Detector: UV 254/220 nm. The fractions containing the desired productwere collected at 40% B and concentrated under reduced pressure toafford3-[3-methyl-2-oxo-5-[(4-oxocyclohexyl)methyl]-1,3-benzodiazol-1-yl]piperidine-2,6-dione(570 mg, 64%) as a white solid: ¹H NMR (300 MHz, CD3OD) δ 7.02 (d, J=7.1Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 5.34-5.31 (m, 1H), 4.88-4.86 (m, 2H),3.45-3.41 (m 3H), 3.32-3.31 (m, 1H), 2.98-2.76 (m, 2H), 2.60 (d, J=6.7Hz, 2H), 2.01-1.96 (m, 2H), 1.61 (d, J=11.0 Hz, 3H), 1.28-1.25 (m, 3H);LC/MS (ESI, m/z): [(M+1)]⁺=370.20.

Step 2:3-[3-methyl-5-[(4-methylidenecyclohexyl)methyl]-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione.To a stirred solution of methyltriphenylphosphanium bromide (2.27 g,6.36 mmol) in THF (10 mL) was added t-BuOK (713 mg, 6.36 mmol) inportions at 0° C. under nitrogen atmosphere and stirring for 30 min. Tothe above mixture was added3-[3-methyl-2-oxo-5-[(4-oxocyclohexyl)methyl]-1,3-benzodiazol-1-yl]piperidine-2,6-dione(470 mg, 1.27 mmol) in THF (5 mL) at 0° C. The resulting mixture wasstirred for additional 1 h at ambient temperature. The mixture wasacidified to pH 6 with 1 N HCl. The resulting mixture was filtered, thefiltered cake was washed with DCM (3×20 mL). The filtrate wasconcentrated under reduced pressure. The crude product was purified byreverse phase flash chromatography with the following conditions:Column: Spherical C18 Column, 20-40 um, 120 g; Mobile Phase A: Water(plus 0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50%B to 80% B in 25 min Detector: UV 254/220 nm. The fractions containingthe desired product were collected at 70% B and concentrated underreduced pressure to afford3-[3-methyl-5-[(4-methylidenecyclohexyl)methyl]-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione(410 mg, 88%) as a white solid: ¹H NMR (300 MHz, CDCl3) δ 8.05 (d,J=26.4 Hz, 1H), 6.90-6.81 (m, 2H), 6.72 (d, J=8.0 Hz, 1H), 5.38-5.17 (m,2H), 4.65-4.58 (m, 1H), 3.46-3.43 (m, 3H), 3.00-2.70 (m, 3H), 2.60-2.58(m, 2H), 2.31-2.29 (m, 2H), 2.01-1.99 (m 2H), 1.80 (d, J=14.0 Hz, 3H),1.28-1.26 (m, 1H), 1.12-1.10 (m 1H); LC/MS (ESI, m/z): [(M+1)]⁺=368.25.

Step 3: tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-[(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexylidene)methyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate. To a stirredsolution of3-[3-methyl-5-[(4-methylidenecyclohexyl)methyl]-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione(200 mg, 0.55 mmol) and tert-butylN-[(2S,11S)-6-bromo-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (783 mg, 1.09mmol) in DMA (5 mL) were added Pd(DTBPF)C12 (36 mg, 0.054 mmol) and TEA(165 mg, 1.63 mmol) at ambient temperature. The resulting mixture wasstirred for 16 h at 110° C. under nitrogen atmosphere. After coolingdown to ambient temperature, the mixture was purified by reverse phaseflash chromatography with the following conditions: Column: SphericalC18 Column, 20-40 um, 120 g; Mobile Phase A: Water (plus 0.1% HOAc),Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 60% B in20 min; Detector: UV 254/220 nm. The fractions containing the desiredproduct were collected at 56% B and concentrated under reduced pressureto afford tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-[(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexylidene)methyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (100 mg, 19%) asa brown solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.79 (d, J=8.2Hz, 1H), 8.22-8.15 (m, 1H), 7.30-7.23 (m, 11H), 7.02-6.68 (m, 4H),6.86-6.84 (m, 3H), 6.77-6.74 (m, 1H), 6.30-6.05 (m, 2H), 5.35-5.33 (m,1H), 5.09 (d, J=10.2 Hz, 1H), 4.33-4.31 (m, 1H), 4.04 (d, J=6.9 Hz, 1H),2.94-2.89 (m, 5H), 2.70-2.67 (m, 3H), 2.44-2.41 (m, 1H), 2.33-2.30 (m,1H), 2.26-1.84 (m, 9H), 1.80-1.76 (m, 4H), 1.38 (s, 9H), 1.30-0.81 (m,4H); LC/MS (ESI, m/z): [(M+1)]⁺=1005.40.

Step 4: tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-[(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl)methyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate. To a stirredsolution of tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-[(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexylidene)methyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (200 mg, 0.20mmol) in THF (8 mL) was added Pd/C (50 mg, 10% wt) at room temperature.The resulting mixture was stirred for 16 h at room temperature underhydrogen atmosphere (1.5 atm). The resulting mixture was filtered, thefiltered cake was washed with MeOH (5×25 mL). The filtrate wasconcentrated under reduced pressure. The residue was purified by reversephase flash chromatography with the following conditions: Column:Spherical C18 Column, 20-40 um, 120 g; Mobile Phase A: Water (plus 0.1%HOAc v/v), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to50% B in 25 min; Detector: UV 254/220 nm. The fractions containing thedesired product were collected at 40% B and concentrated under reducedpressure to afford tert-butylN-[(2S,11S)-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-[(4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl)methyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (170 mg, 85%) asa white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.75-8.73 (m,1H), 8.31-8.12 (m, 1H), 7.36-7.19 (m, 11H), 7.08-6.94 (m, 3H), 6.89-6.75(m, 3H), 6.11-6.04 (m, 1H), 5.38-5.30 (m, 1H), 5.08-5.06 (m, 1H),4.35-4.29 (m, 1H), 4.05-3.98 (m, 1H), 3.46 (d, J=1.8 Hz, 2H), 3.09-2.82(m, 4H), 2.76-2.54 (m, 4H), 2.38-2.36 (m, 1H), 2.13-1.96 (m, 5H),1.93-1.87 (m, 1H), 1.79-1.77 (m, 1H), 1.64 (d, J=8.6 Hz, 2H), 1.56-1.52(m, 2H), 1.47-1.40 (m, 3H) 1.38 (s, 9H), 1.30-1.03 (m, 6H), 0.96-0.75(m, 3H); LC/MS (ESI, m/z): [(M+1)]⁺=1007.45.

(4S,5R)-4-[[(2S,11S)-11-amino-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-2-yl]formamido]-5-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)hexanamideacetate (Intermediate J)

A solution of 9H-fluoren-9-ylmethylN-[(2S,11S)-2-[[(3S,4R)-1-carbamoyl-4-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)pentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (200 mg, 0.18mmol) in DMF (3.50 mL) was treated with diethylamine (0.70 mL) for 20min at room temperature under nitrogen atmosphere. The mixture wasacidified to pH=5 with AcOH. The mixture was concentrated under reducedpressure. The residue was purified by reversed phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 120 g; Eluent A: Water (plus 10 mmol/LAcOH); Eluent B: ACN;Gradient: 15%-35% B in 20 min; Flow rate: 50 mL/min; Detector: UV220/200 nm; desired fractions were collected at 28% B and concentratedunder reduced pressure to afford the title compound as a white solid (85mg, 54%): ¹H NMR (400 MHz, DMSO-d₄) δ 7.80 (d, J=9.3 Hz, 1H), 7.18 (d,J=7.9 Hz, 2H), 7.15-7.09 (m, 2H), 7.06-6.97 (m, 4H), 6.96-6.84 (m, 2H),6.67 (s, 1H), 5.33 (dd, J=12.6, 5.4 Hz, 1H), 5.05 (d, J=10.8 Hz, 1H),4.41 (s, 2H), 3.84-3.73 (m, 1H), 3.55 (d, J=5.0 Hz, 2H), 3.51 (s, 3H),3.46-3.35 (m, 4H), 3.06-2.95 (m, 2H), 2.92-2.80 (m, 2H), 2.73-2.57 (m,5H), 2.47-2.37 (m, 3H), 2.12-1.93 (m, 4H), 1.90 (s, 3H), 1.89-1.70 (m,5H), 1.62-1.47 (m, 2H), 1.08 (d, J=6.3 Hz, 3H); MS (ESI, m/z):[(M+1)]⁺=866.50.

The following intermediates in Table 52 were synthesized according tothe procedure to prepare Intermediate J.

TABLE 52 Characterization data for intermediates prepare according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H NMR J1

(4S,5R)-4- [[(1R,2S,5S)-3- aminohexanoyl]-3- azabicyclo [3.1.0]hexan-2-yl]formamido]- 5-[[4-(3-[2-[2- (2-[3-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-1,3- benzodiazol-5-yl]propoxy]ethoxy) ethoxy]acetamido] propyl)phenyl] methoxy] hexanamideacetate 961.6 (400 MHz, DMSO-d₆) δ 8.07 (d, J = 9.2 Hz, 1H), 7.71 (t, J= 5.8 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.26-7.20 (m, 2H), 7.18-7.11(m, 2H), 7.10-6.97 (m, 3H), 6.87 (dd, J = 8.2, 1.6 Hz, 1H), 6.66 (s,1H), 5.34 (dd, J = 12.6, 5.3 Hz, 1H), 4.52-4.33 (m, 3H), 3.88 (s, 2H),3.83 (dd, J = 9.8, 5.3 Hz, 1H), 3.75-3.65 (m, 1H), 3.60-3.49 (m, 8H),3.53-3.37 (m, 3H), 3.40-3.34 (m, 1H), 3.32 (s, 3H), 3.11 (q, J = 6.7 Hz,2H), 2.98-2.84 (m, 1H), 2.77-2.52 (m, 8H), 2.19-2.07 (m, 1H), 2.05-1.96(m, 1H), 1.90 (s, 3H), 1.87-1.77 (m, 2H), 1.77-1.66 (m, 2H), 1.56-1.40(m, 2H), 1.29-1.20 (m, 5H), 1.10 (dd, J = 12.7, 6.2 Hz, 3H), 0.89- 0.81(m, 3H), 0.70 (d, J = 4.6 Hz, 1H), 0.55 (s, 1H). J2

(4S,5R)-4- [[(1R,2S,5S)-3- [(2S)-2- aminohexanoyl]-3- azabicyclo[3.1.0]hexan-2-yl] formamido]- 5-[(4-[3-[2-(2-[3-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H- 1,3-benzodiazol-5-yl]propoxy]ethoxy) acetamido]propyl] phenyl)methoxy] hexanamide acetate917.7 (400 MHz, DMSO-d₆) δ 8.07 (d, J = 9.2 Hz, 1H), 7.72 (t, J = 5.9Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.23 (dd, J = 7.9, 3.8 Hz, 2H),7.18-7.10 (m, 2H), 7.07 (s, 1H), 7.05-6.97 (m, 2H), 6.88 (dd, J = 8.1,1.6 Hz, 1H), 6.66 (s, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.50-4.33(m, 3H), 3.90 (s, 2H), 3.83 (dd, J = 9.9, 5.3 Hz, 1H), 3.70 (d, J = 9.2Hz, 1H), 3.60 917.7 (dd, J = 6.1, 3.4 Hz, 2H), 3.58- 3.51 (m, 3H),3.49-3.30 (m, 4H), 3.12 (q, J = 6.7 2H), 2.99-2.84 (m, 2H), 2.76-2.58(m, 4H), 2.57-2.52 (m, 4H), 2.20-1.95 (m, 3H), 1.90 (s, 3H), 1.87-1.78(m, 2H), 1.75-1.64 (m, 2H), 1.60-1.39 (m, 1H), 1.37-1.16 (m, 6H), 1.10(dd, J = 12.6, 6.2 Hz, 3H), 0.85 (t, J = 6.8 Hz, = 3H), 0.71 (q, J = 4.4Hz, 1H), 0.55 (d, J 4.6 Hz, 1H). J3

N-[3-[4-([[(2R,3S)- 3-[[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ({circumflex over ( )})}[4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxylmethyl) phenyl]propyl]-15-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H- 1,3-benzodiazol-5- yl]-3,6,9,12-tetraoxapenta- decanamide acetate 1011.7 (400 MHz, DMSO-d₆) δ 7.82 (d, J= 9.3 Hz, 1H), 7.72 (t, J = 6.1 Hz, 1H), 7.22- 7.16 (m, 2H), 7.12 (d, J= 7.8 Hz, 2H), 7.04-6.99 (m, 3H), 6.93 (dd, J = 8.1, 6.7 Hz, 1H), 6.86(d, J = 8.1 Hz, 1H), 6.69 (s, 1H), 5.34 (dd, J = 12.8, 5.4 Hz, 1H), 5.06(dd, J = 11.0, 3.1 Hz, 1H), 4.47- 4.35 (m, 2H), 3.87 (s, 2H), 3.83-3.72(m, 1H), 3.57 (s, 4H), 3.53 (m, 5H), 3.50-3.45 (m, 2H), 3.43-3.32 (m,8H), 3.15-3.09 (m, 2H), 3.07-2.98 (m, 1H), 2.90 (s, 2H), 2.86 (d, J =3.9 Hz, 1H), 2.73-2.61 (m, 2H), 2.56 (d, J = 7.5 Hz, 1H), 2.13-1.85 (m,10H), 1.84-1.77 (m, 2H), 1.75-1.67 (m, 2H), 1.63-1.50 (m, 1H), 1.09 (dd,J = 9.1, 6.7 Hz, 3H). J4

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[[4-(3-[2-[2-(2-[3- [1-(2,6 dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propoxy]ethoxy) ethoxy]acetamido]propyl)phenyl] methoxy] hexanamide acetate 967.7 (400 MHz, DMSO-d₆) δ7.91-7.76 (m, 1H), 7.71 (t, J = 5.7 Hz, 1H), 7.16 (m, 3H), 7.10 (d, J =7.9 Hz, 2H), 7.04-6.95 (m, 4H), 6.91 (dd, J = 8.2, 6.6 Hz, 1H), 6.85(dd, J = 8.1, 1.6 Hz, 1H), 6.67 (s, 1H), 5.32 (dd, J = 12.7, 5.4 Hz,1H), 5.04 (dd, J = 11.0, 3.2 Hz, 1H), 4.44- 4.34 (m, 2H), 3.87 (s, 2H),3.84-3.72 (m, 1H), 3.60-3.51 (m, 6H), 3.55-3.45 (m, 2H), 3.45-3.34 (m,11H), 3.11 (q, J = 6.7 Hz, 2H), 3.06-2.97 (m, 1H), 2.90- 2.78 (m, 2H),2.75-2.57 (m, 4H), 2.56- 2.50 (m, 2H), 2.10-1.94 (m, 3H), 1.93- 1.86 (m,4H), 1.85-1.63 (m, 4H), 1.61- 1.49 (d, J = 9.7 Hz, 1H), 1.06 (d, J = 6.3Hz, 3H). J5

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[2-(2-[3-[1- (2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- 1,3-benzodiazol-5- yl]propoxy]ethoxy)acetamido]propyl] phenyl)methoxy] hexanamide acetate 923.5 (400 MHz,DMSO-d₆) δ 7.82 (d, J = 9.2 Hz, 1H), 7.74 J = 6.0 Hz, 1H), 7.17 (d, J =7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 7.05-6.97 (m, 4H), 6.92 (dd, J =8.2, 6.6 Hz, 1H), 6.86 (dd, J = 8.1, 1.5 Hz, 1H), 6.69 (s, 1H), 5.34(dd, J = 12.8, 5.3 Hz, 1H), 5.06 (d, J = 10.8 Hz, 1H), 4.41 (s, 2H),3.90 (s, 2H), 3.84-3.73 (m, 1H), 3.61 (dd, J = 6.0, 3.4 Hz, 2H), 3.56(dd, J = 5.8, 3.2 Hz, 2H), 3.49-3.37 (m, 4H), 3.37-3.28 (m, 8H), 3.13(d, J = 6.3 Hz, 2H), 3.06-2.98 (m, 2H), 2.98-2.78 (m, 2H), 2.76-2.60 (m,4H), 2.57-2.50 (m, 2H), 2.15-1.93 (m, 2H), 1.91 (s, 3H), 1.88-1.67 (m,4H), 1.56 (d, J = 9.6 Hz, 1H), 1.08 (d, J = 6.2 Hz, 3H). J6

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-[2-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propoxy]acetamido) propyl]phenyl]methoxy)hexanamide acetate 879.7 (400 MHz, DMSO-d₆) δ 7.82 (d, J = 9.2Hz, 1H), 7.75 (t, J = 6.0 Hz, 1H), 7.22- 7.09 (m, 5H), 7.08-6.96 (m,4H), 6.95- 6.84 (m, 2H), 6.69 (s, 1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H),5.05 (dd, J = 11.0, 3.2 Hz, 1H), 4.46-4.37 (m, 2H), 3.84 (s, 2H),3.82-3.71 (m, 1H), 3.50-3.32 (m, 9H), 3.13 (q, J = 6.7 Hz, 2H), 3.03 (d,J = 13.4 Hz, 2H), 2.86 (t, J = 16.2 Hz, 2H), 2.78-2.58 (m, 4H),2.56-2.50 (m, 2H), 2.13-1.94 (m, 5H), 1.93-1.83 (m, 5H), 1.73 (q, J =7.4 Hz, 2H), 1.61-1.45 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H). J7

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[[4-(3-[3[1(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5- yl]propanamido] propyl)phenyl]methoxy] hexanamide acetate 835.6 (400 MHz, DMSO-d₆) δ 7.90-7.80 (m,2H), 7.18 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 7.06-6.98 (m,4H), 6.97- 6.88 (m, 2H), 6.70 (s, 1H), 5.33 (dd, J = 12.7, 5.3 Hz, 1H),5.07 (dd, J = 11.0, 3.2 835.6 Hz, 1H), 4.48-4.33 (m, 2H), 3.84-3.73 (m,1H), 3.52-3.32 (m, 9H), 3.09-2.99 (m, 4H), 2.92-2.82 (m, 4H), 2.75-2.56(m, 2H), 2.41 (t, J = 7.7 Hz, 2H), 2.12- 1.87 (m, 7H), 1.85-1.73 (m,1H), 1.72- 1.43 (m, 3H), 1.09 (d, J = 6.2 Hz, 3H). J8

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca- 4(13),5,7-trien-2-yl]formamido]-5- [4-(3-[2-[2-(2-[3- [3-methyl-1-(1- methyl-2,-dioxopiperidin-3- yl)-2-oxo-1,3- benzodiazol-5- yl]propoxy]ethoxy)ethoxy]acetamido] propyl)phenyl] methoxy] hexanamide acetate 981.6 (400MHz, DMSO-d₆) δ 7.80 (d, J = 9.3 Hz, 1H), 7.71 (t, J = 5.8 Hz, 1H),7.21- 7.08 (m, 5H), 7.06-6.97 (m, 4H), 6.92 (dd, J = 8.2, 6.6 Hz, 1H),6.85 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 5.40 (dd, J = 13.0, 5.3 Hz, 1H),5.06 (dd, J = 11.0, 3.2 Hz, 1H), 4.46-4.35 (m, 2H), 3.88 (s, 2H),3.83-3.70 (m, 1H), 3.62-3.53 (m, 6H), 3.53-3.34 (m, 10H), 3.32 (s, 3H),3.12 (q, J = 6.8 Hz, 2H), 3.04 (s, 3H), 2.89-2.70 (m, 2H), 2.70-2.60 (m,3H), 2.55-2.50 (m, 2H), 2.12-1.94 (m, 3H), 1.91 (s, 6H), 1.87-1.67 (m,4H), 1.62- 1.48 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H). J9

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[2-(2-[3-[3- methyl-1-(1-methyl- 2,6-dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]propoxy]ethoxy) acetamido]propyl]phenyl)methoxy] hexanamide acetate 937.5 (400 MHz, DMSO-d₆) δ 7.80 (d, J= 9.1 Hz, 1H), 7.73 (d, J = 5.9 Hz, 1H), 7.21- 7.15 (m, 3H), 7.11 (d, J= 8.0 Hz, 2H), 7.06-6.98 (m, 4H), 6.92 (dd, J = 8.2, 6.6 Hz, 1H), 6.85(d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 5.40 (dd, J = 13.0, 5.3 Hz, 1H), 5.05(dd, J = 10.9, 3.3 Hz, 1H), 4.46- 937.5 4.35 (m, 2H), 3.90 (s, 2H),3.83-3.72 (m, 1H), 3.61 (dd, J = 6.1, 3.4 Hz, 2H), 3.58-3.53 (m, 2H),3.47-3.39 (m, 4H), 3.38-3.28 (m, 3H), 3.13 (q, J = 6.6 Hz, 2H),3.07-2.90 (m, 6H), 2.89-2.78 (m, 2H), 2.77-2.61 (m, 4H), 2.55-2.50 (m,2H), 2.08-1.94 (m, 5H), 1.91 (s, 3H), 1.89-1.68 (m, 5H), 1.62-1.48 (m,1H), 1.08 (d, J = 6.2 Hz, 3H). J10

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[[4-(3-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]propoxy]propyl) phenyl]methoxy] hexanamide acetate822.6 (400 MHz, DMSO-d₆) δ 7.79 (d, J = 9.3 Hz, 1H), 7.19 (d, J = 7.8Hz, 2H), 7.16- 7.10 (m, 3H), 7.04-6.95 (m, 4H), 6.94- 6.85 (m, 2H), 6.66(s, 1H), 5.36 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 9.1 Hz, 1H), 4.40 (d, J= 12.4 Hz, 2H), 3.83-3.70 (m, 1H), 3.57 (s, 3H), 3.46-3.35 (m, 6H),3.02-2.93 (m, 3H), 2.93-2.80 (m, 1H), 2.67-2.58 (m, 4H), 2.55-2.50 (m,2H), 2.07-1.93 (m, 6H), 1.90 (s, 3H), 1.87- 1.73 (m, 5H), 1.61-1.48 (m,1H), 1.08 (d, J = 6.2 Hz, 3H). J11

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-(2-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]propoxy]ethoxy) propyl]phenyl] methoxy) hexanamideacetate 866.6 (400 MHz, DMSO-d₆) δ 7.79 (d, J = 9.2 Hz, 1H), 7.22-7.10(m, 6H), 7.01 (d, J = 7.5 Hz, 2H), 6.98-6.89 (m, 3H), 6.8 (dt, J = 5.5,3.4 Hz, 1H), 6.67 (s, 1H), 5.36 (dd, J = 12.7, 5.4 Hz, 1H), 5.05 (d d, J= 10.9, 3.2 Hz, 1H), 4.41 (d, J = 3.3 Hz, 2H), 3.82-3.73 (m, 1H),3.58-3.30 (m, 20H), 3.07-2.80 (m, 5H), 2.76-2.57 (m, 3H), 2.12-1.92 (d,J = 14.5 Hz, 2H), 1.89 (s, 3H), 1.86-1.73 (m, 4H), 1.61-1.49 (m, 1H),1.08 (d, J = 6.4 Hz, 3H). J12

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-(2-[3-[3- methyl-1-(1-methyl- 2,6-dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-4- yl]propoxy]ethoxy) propyl]phenyl]methoxy) hexanamide acetate 880.6 (400 MHz, DMSO-d₆) δ 7.79 (d, J= 9.2 Hz, 1H), 7.21-7.08 (m, 3H), 7.04-6.90 (m, 4H), 6.89 (s, 1H), 6.66(s, 1H), 5.43 (d, J = 13.0 Hz, 1H), 5.05 (d, J = 10.0 Hz, 1H), 4.44-4.35(m, 2H), 3.84-3.69 (m, 1H), 3.56 (d, J = 3.4 Hz, 3H), 3.50- 3.43 (m,3H), 3.48-3.27 (m, 9H), 3.03 (d, J = 3.2 Hz, 3H), 3.02-2.90 (m, 2H),2.95 (m, 4H), 2.88-2.77 (m, 2H), 2.73 (d, J = 12.6 Hz, 1H), 2.61 (s,2H), 2.05- 1.94 (m,4H), 1.89 (s, 3H), 1.86-1.68 (m, 4H), 1.61-1.46 (m,1H), 1.07 (dd, J = 6.4, 2.9 Hz, 3H). J13

(4S,5R)-4- [[(2S,11S)-11- Amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-(3-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]propoxy]propoxy) propyl]phenyl] methoxy)hexanamide acetate 880.5 Crude to next step without further purificationJ14

(4S,5R)-4- [(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-(3-[3-[1(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]propoxy]propoxy) propyl]phenyl] methoxy)hexanamide acetate 880.6 Crude to next step without further purificationJ15

(4S,5R)-4- [[(2S,11S)-11- Amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-(4-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]propoxy]butoxy) propyl]phenyl] methoxy) hexanamidacetate 894.7 (400 MHz, DMSO-d₆) δ 7.81 (d, J = 9.3 Hz, 1H), 7.21-7.09(m, 5H), 7.05-6.9 7 (m, 4H), 6.97-6.89 (m, 1H), 6.87 (d, J = 8.1 Hz,1H), 6.68 (s, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 5.06 (dd, J = 10.9,3.2 Hz, 1H), 4.41 (s, 2H), 3.85-3.72 (m, 1H), 3.52-3.45 (m, 1H),3.48-3.30 (m, 15H), 3.02 (t, J = 5.5 Hz, 2H), 2.96-2.80 (m, 2H),2.76-2.57 (m, 6H), 2.55-2.50 (m, 2H), 2.08 (dd, J = 10.6, 4.9 Hz, 1H),2.07-1.91 (m, 3H), 1.91 (s, 3H), 1.87-1.72 (m, 5H), 1.60-1.53 (m, 5H),1.08 (d, J = 6.2 Hz, 3H). J16

(4S,5R)-4- [[(2S, 11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- ([4-[3-(4-[3-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]propoxy]butoxy) propyl]phenyl] methoxy)hexanamide acetate 894.6 (400MHz, DMSO-d₆) δ 7.81 (d, J = 9.3 Hz, 1H), 7.22-7.09 (m, 5H), 7.01 (d, J= 7.4 Hz, 2H), 6.99 -6.88 (m, 3H), 6.86 (dd, J = 5.6, 3.3 Hz, 1H), 6.68(s, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 5.06 (dd, J = 11.0, 3.2 Hz,1H), 4.46-4.35 (m, 2H), 3.79 (t, J = 5.2 Hz, 1H), 3.56 (s, 3H),3.46-3.32 (m, 13H), 3.07-2.80 (m, 6H), 2.72 (td, J = 12.8, 4.4 Hz, 1H),2.65-2.54 (m, 3H), 2.13-1.93 (m, 3H), 1.90 (s, 3H), 1.86-1.71 (m, 5H),1.64- 1.48 (m, 5H), 1.08 (d, J = 6.3 Hz, 3H). J17

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3[(6-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]propoxy]hexyl) oxy]propyl]phenyl)methoxy]hexanamide acetate 908.7 (400 MHz, DMSO-d₆) δ 7.80 (d, J = 9.2Hz, 1H), 7.22-7.15 (m, 3H), 7.11 (d, J = 7.9 Hz, 2H), 7.05-6.97 (m, 4H),6.92 (dd, J = 8.1, 6.7 Hz, 1H), 6.86 (dd, J = 8.1, 1.6 Hz, 1H), 6.68 (s,1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 5.05 (dd, J = 11.0, 3.2 Hz, 1H),4.41 (d, J = 2.2 Hz, 2H), 3.82-3.76 (m, 1H), 3.47-3.40 (m, 2H),3.43-3.29 (m, 13H), 3.07-2.98 (m, 2H), 2.95-2.79 (m, 2H), 2.77-2.55 (m,7H), 2.13-1.93 (m, 3H), 1.90 (s, 3H), 1.85- 1.73 (m, 5H), 1.61-1.46 (m,5H), 1.43- 1.31 (m, 2H), 1.08 (d, J = 6.3 Hz, 3H). J18

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[(5-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]propoxy] pentypoxylpropyl] phenyl)methoxylhexanamide 908.7 (400 MHz, CD₃OD) δ 7.22 (d, J = 7.6 Hz, 2H),7.13 (d, J = 7.7 Hz, 2H), 7.10- 6.99 (m, 4H), 6.99-6.91 (m, 2H), 5.38-5.27(m, 1H), 5.13 (d, J = 11.2 Hz, 1H), 4.48 (t, J = 9.1 Hz, 2H),4.03-3.95 (m, 1H), 3.73 (d, J = 9.8 Hz, 1H), 3.69-3.62 (m, 4H),3.61-3.54 (m, 1H), 3.53-3.40 (m, 6H), 3.40-3.26 (m, 6H), 3.16 (t, J =6.5 Hz, 2H), 3.10-2.87 (m, 4H), 2.80 (d, J = 14.7 Hz, 2H), 2.69 (t, J =7.7 Hz, 2H), 2.37-2.20 (m, 2H), 2.20-2.07 (m, 2H), 1.96-1.83 (m, 7H),1.77-1.58 (m, 4H), 1.52 (d, J = 6.7 Hz, 1H), 1.20 (d, J = 6.2 Hz, 3H).J19

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[(6-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]propoxy]hexyl) oxy]propyl]phenyl)methoxy]hexanamide acetate 922.4 (400 MHz, CD₃OD) δ 7.24 (d, J = 7.8 Hz,2H), 7.17-7.01 (m, 6H), 7.01 (d, J = 4.4 Hz, 1H), 7.01-6.93 (m, 1H),5.31 (dd, J = 12.5, 5.4 Hz, 1H), 5.15 (dd, J = 10.9, 3.6 Hz, 1H),4.56-4.44 (m, 2H), 4.01 (dt, J = 11.2, 3.7 Hz, 1H), 3.87-3.80 (m, 1H),3.58 (p, J = 6.2 Hz, 1H), 3.51- 3.38 (m, 11H), 3.36-3.29 (m, 6H), 3.18(t, J = 6.7 Hz, 2H), 3.01 (dd, J = 16.7, 3.6 Hz, 1H), 2.95-2.86 (m, 1H),2.84-2.72 (m, 4H), 2.68 (t, J = 7.6 Hz, 2H), 2.36-2.20 (m, 2H), 2.17(dd, J = 11.3, 5.7 Hz, 1H), 2.01 (dd, J = 13.1, 7.2 Hz, 1H), 1.93 (s,3H), 1.97-1.81 (m, 4H), 1.76-1.65 (m, 1H), 1.64-1.55 (m, 1H), 1.50-1.38(m, 4H), 1.20 (d, J = 6.3 Hz, 3H). J20

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- yl]formamido]-5- 4(13),5,7-trien-2-[(4-[3-[((6-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]propoxy]hexyl) oxy]propyl]phenyl)methoxy]hexanamide acetate [(M/2 + 1)]⁺ = 462.0 (400 MHz, DMSO-d₆) δ7.81 (d, J = 9.3 Hz, 1H), 7.22-7.15 (m, 3H), 7.11 (d, J = 7.9 Hz, 2H),7.01 (d, J = 7.4 Hz, 2H), 6.99-6.88 (m, 3H), 6.86 (dd, J = 5.5, 3.4 Hz,1H), 6.68 (s, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H), 5.06 (dd, J = 10.9,3.2 Hz, 1H), 4.46-4.35 (m, 2H), 3.81-3.75 (m, 1H), 3.49-3.25 (m, 12H),3.07-2.78 (m, 6H), 2.72 (td, J = 12.8, 4.4 Hz, 1H), 2.66-2.59 (m, 1H),2.58 (d, J = 7.9 Hz, 2H), 2.55-2.50 (m, 2H), 2.13-2.05 (m, 1H),2.03-1.91 (m, 2H), 1.90 (s, 3H), 1.88-1.71 (m, 6H), 1.56-1.47 (m, 6H),1.40-1.30 (m, 4H), 1.08 (d, J = 6.2 Hz, 3H). J21

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[(6-[3-[3- methyl-1-(1-methyl- 2,6-dioxopiperidin-3-yl)-2-oxo-1,3- benzodiazol-5- yl]propoxy]hexyl) oxy]propyl]phenyl)methoxy]hexanamide acetate 936.7 (400 MHz, DMSO-d₆) δ 7.79 (d, J = 9.3Hz, 1H), 7.27-7.08 (m, 5H), 7.07-6.99 (m, 4H), 6.92 (dd, J = 8.2, 6.7Hz, 1H), 6.85 (dd, J = 8.1, 1.6 Hz, 1H), 6.66 (s, 1H), 5.40 (dd, J =13.0, 5.3 Hz, 1H), 5.06 (dd, J = 10.9, 3.3 Hz, 1H), 4.47- 4.36 (m, 2H),3.84-3.73 (m, 1H), 3.49- 3.40 (m, 1H), 3.40-3.25 (m, 16H), 3.06- 2.91(m, 4H), 2.88-2.71 (m, 2H), 2.70- 2.56 (m, 4H), 2.55-2.50 (m, 2H), 2.12-1.95 (m, 2H), 1.91 (s, 3H), 1.86-1.73 (m, 5H), 1.60-1.46 (m, 6H),1.37-1.30 (m, 4H), 1.08 (d, J = 6.2 Hz, 3H). J22

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[(7-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]propoxy] heptypoxylpropyl] phenyl)methoxylhexanamide acetate 936.6 (400 MHz, DMSO-d₆) δ 7.81 (d, J = 9.3Hz, 1H), 7.23-7.15 (m, 3H), 7.11 (d, J = 7.8 Hz, 2H), 7.06-6.97 (m, 4H),6.96- 6.89 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.68 (s, 1H), 5.34 (dd, J= 12.7, 5.3 Hz, 1H), 5.06 (dd, J = 11.0, 3.2 Hz, 1H), 4.41 (d, J = 2.1Hz, 2H), 3.84-3.73 (m, 1H), 3.49-3.31 (m, 12H), 3.03 (q, J = 5.9, 5.2Hz, 2H), 2.87 (td, J = 16.5, 4.0 Hz, 2H), 2.76-2.55 (m, 6H), 2.55-2.50(m, 2H), 2.12-2.03 (m, 1H), 2.05-1.93 (m, 4H), 1.90 (s, 3H), 1.85-1.70(m, 5H), 1.61-1.44 (m, 5H), 1.37-1.22 (m, 6H), 1.08 (d, J = 6.2 Hz, 3H).J23

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[(8-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]propoxy]octyl) oxy]propyl]phenyl)methoxy]hexanamide acetate 950.7 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),8.40 (d, J = 5.0 Hz, 3H), 8.01 (d, J = 9.2 Hz, 1H), 7.21-7.13 (m, 3H),7.13-7.02 (m, 4H), 7.05-6.96 (m, 3H), 6.86 (dd, J = 8.2, 1.6 Hz, 1H),6.74 (s, 1H), 5.34 (dd, J = 12.8, 5.3 Hz, 1H), 5.13 (dd, J = 11.0, 3.0Hz, 1H), 4.40 (s, 2H), 4.20 (d, J = 8.1 Hz, 1H), 4.11-3.94 (m, 3H), 3.81(s, 1H), 3.49-3.43 (m, 2H), 3.43-3.29 (m, 11H), 3.14 (d, J = 6.1 Hz,2H), 2.87 (dd, J = 16.7, 9.7 Hz, 2H), 2.67-2.53 (m, 6H), 2.19 (d, J =14.3 Hz, 1H), 2.15- 1.96 (m, 2H), 1.85-1.69 (m, 5H), 1.67- 1.43 (m, 6H),1.29 (s, 9H), 1.09 (d, J = 6.2 Hz, 3H). J24

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[2-(2-[3-[1- (2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]propoxy]ethoxy) ethoxylpropyl]phenyl)methoxy]hexanamide acetate [(M/2 + 1)]⁺ = 456.0 Used in the next stepwithout further purification J25

(4S,5R)-4- [[(2S,11S)-11- Amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[3-[2-(2-[3-[1- (2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3-benzodiazol-4- yl]propoxy]ethoxy) ethoxylpropyl]phenyl)methoxy]hexanamide acetate 910.7 (400 MHz, DMSO-d₆) δ 7.80 (d, J = 9.3Hz, 1H), 7.25-7.07 (m, 5H), 7.02 (d, J = 7.4 Hz, 2H), 6.98-6.95 (m, 2H),6.95- 6.91 (m, 1H), 6.87 (dd, J = 5.8, 3.1 Hz, 1H), 6.67 (s, 1H), 5.36(dd, J = 12.5, 5.4 Hz, 1H), 5.06 (dd, J = 11.0, 3.2 Hz, 1H), 4.47-4.35(m, 2H), 3.83-3.71 (m, 1H), 3.61-3.42 (m, 16H), 3.41-3.33 (m, 3H),3.06-2.80 (m, 6H), 2.76-2.55 (m, 4H), 2.13-1.94 (m, 4H), 1.91 (s, 3H),1.86- 1.73 (m, 5H), 1.61-1.50 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H). J26

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[16-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5-yl]- 4,7,10,13- tetraoxahexadecan- 1-yl]phenyl)methoxy] hexanamide acetate 954.7 (400 MHz, DMSO-d₆) δ 7.83(d, J = 9.3 Hz, 1H), 7.22-7.15 (m, 3H), 7.12 (d, J = 7.9 Hz, 2H),7.07-6.97 (m, 4H), 6.93 (dd, J = 8.2, 6.7 Hz, 1H), 6.87 (dd, J = 8.1,1.6 Hz, 1H), 6.70 (s, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 5.06 (dd, J= 10.9, 3.2 Hz, 1H), 4.41 (d, J = 2.0 Hz, 2H), 3.83-3.72 (m, 1H),3.58-3.32 (m, 22H), 3.04 (d, J = 12.8 Hz, 2H), 2.93-2.80 (m, 2H),2.78-2.53 (m, 6H), 2.55-2.50 (m, 2H), 2.13-1.94 (m, 3H), 1.91 (s, 3H),1.84-1.70 (m, 5H), 1.62-1.49 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H). J27

(2S,4R)-1-[(2S)-2- [[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl] formamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamideacetate 921.4 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.60 (d, J = 6.0 Hz,1H), 7.90 (d, J = 9.1 Hz, 1H), 7.86-7.76 (m, 3H), 7.47-7.33 (m, 6H),7.17 (s, 1H), 7.02 (d, J = 7.5 Hz, 2H), 6.96-6.88 (m, 1H), 6.68 (s, 1H),5.16 (s, 1H), 5.10-5.02 (m, 1H), 4.78 (d, J = 9.0 Hz, 1H), 4.53 (s, 2H),4.48 (d, J = 8.0 Hz, 1H), 4.47-4.39 (m, 1H), 4.39 (s, 1H), 4.30-4.21 (m,1H), 3.88-3.78 (m, 1H), 3.74 (s, 2H), 3.51- 3.39 (m, 2H), 3.07-2.97 (m,2H), 2.84 (d, J = 14.9 Hz, 1H), 2.45 (s, 3H), 2.13- 2.02 (m, 3H),2.00-1.94 (m, 3H), 1.91 (s, 3H), 1.84-1.71 (m, 1H), 1.64-1.50 (m, 1H),1.11 (d, J = 6.3 Hz, 3H), 1.05 (s, 9H). J28

(2S,4R)-1-[(2S)-2- [2-[4-([[(2R,3S)-3- [(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carboylpentan-2-yl]oxy]methyl)phenyl] acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate [M/2 + 1]⁺ = 468.5 (400 MHz, DMSO-d₆)δ 8.99 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.82(d, J = 9.3 Hz, 1H), 7.47- 7.34 (m, 4H), 7.28-7.14 (m, 5H), 7.02 (dd, J= 7.2, 4.6 Hz, 2H), 6.97-6.89 (m, 1H), 6.68 (s, 1H), 5.06 (dd, J = 10.9,3.3 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.49- 4.37 (m, 4H), 4.37-4.32 (m,1H), 4.23 (dd, J = 15.9, 5.4 Hz, 1H), 3.84-3.72(m, 1H), 3.71-3.59 (m,4H), 3.49-3.31 (m, 6H), 3.08-2.99 (m, 2H), 2.89-2.77 (m, 1H), 2.46 (s,3H), 2.13-1.93 (m, 3H), 1.90 (s, 3H), 1.85-1.72 (m, 1H), 1.63- 1.52 (m,1H), 1.08 (d, J = 6.2 Hz, 3H), 0.92 (s, 9H). J29

(2S,4R)-1-[(2,5)-2- [3-[4-([[(2R,3S)-3- [[(2S,11S)-11- Amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]propanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide949.7 (400 MHz, CDCl₃) δ 8.67 (s, 1H), 7.39- 7.29 (m, 5H), 7.19 (d, J =7.8 Hz, 2H), 7.07 (d, J = 4.0 Hz, 1H),7.01 (d, J = 3.7 Hz, 2H), 6.74 (s,1H), 5.99 (s, 1H), 5.09 (d, J = 9.8 Hz, 1H), 4.73-4.52 (m, 4H), 4.43 (d,J = 11.8 Hz, 1H), 4.26 (dd, J = 15.1, 4.4 Hz, 1H), 4.15 (d, J = 11.4 Hz,1H), 3.97-3.89 (m, 1H), 3.68-3.61 (m, 2H), 3.52 (d, J = 10.0 Hz, 1H),3.37 (d, J = 16.5 Hz, 1H), 3.27 (d, J = 10.3 Hz, 1H), 3.14-3.01 (m, 2H),2.86 (dt, J = 13.4, 6.3 Hz, 2H), 2.63-2.51 (m, 3H), 2.48 (s, 3H),2.27-1.97 (m, 5H), 1.93- 1.80 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H), 0.95(s, 9H). J30

(2S,4R)-1-[(2S)-2- (2-[3-[4-([[(2R,3S)- 3-[[(2S,11S)-11- Amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]propoxy] acetamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide993.3 (400 MHz, DMSO-d₆) δ 8.97 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 6.3Hz, 1H), 7.78 (d, J = 9.3 Hz, 1H), 7.47-7.35 (m, 5H), 7.22-7.10 (m, 5H),7.01 (d, J = 7.5 Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.66 (s, 1H), 5.16(d, J = 3.6 Hz, 1H), 5.05 (d, J = 11.7 Hz, 1H), 4.57 (d, J = 9.4 Hz,1H), 4.46 (t, J = 8.2 Hz, 1H), 442-4.32 (m, 4H), 4.31-4.18 (m, 1H), 3.94(s, 2H), 3.84-3.72 (m, 1H), 3.72-3.58 (m, 2H), 3.53-3.38 (m, 4H),3.06-2.96 (m, 2H), 2.85 (d, J = 16.6 Hz, 1H), 2.71-2.60 (m, 3H), 2.42(s, 3H), 2.17-1.70 (m, 9H), 1.62-1.44 (m, 1H), 1.08 (d, J = 6.1 Hz, 3H),0.95 (s, 9H). J31

(2S,4S)-1-[(2S)-2-(2- [3-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)phenyl] propoxy]acetamido)- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate 993.7 (400 MHz, DMSO-d₆) δ 8.97 (s,1H), 8.68 (t, J = 6.0 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.44-7.34 (m,5H), 7.23-7.07 (m, 5H), 7.01 (d, J = 7.5 Hz, 2H), 6.92 (dd, J = 8.1, 6.7Hz, 1H), 6.67 (s, 1H), 5.05 (dd, J = 11.0, 3.2 Hz, 1H), 4.53 (d, J = 9.3Hz, 1H), 4.47-4.35 (m, 4H), 4.33-4.18 (m, 2H), 3.93 (s, 2H), 3.91- 3.84(m, 1H), 3.85-3.70 (m, 1H), 3.60- 3.30 (m, 8H), 3.02 (q, J = 5.9, 5.3Hz, 2H), 2.85 (dd, J = 16.9, 3.2 Hz, 1H), 2.64 (t, J = 7.7 Hz, 2H), 2.42(s, 3H), 2.40-2.29 (m, 1H), 2.11-1.94 (m, 2H), 1.89 (s, 3H), 1.87-1.70(m, 4H), 1.64- 1.46 (m, 1H), 1.07 (d, J = 6.3 Hz, 3H), 0.96 (s, 9H). J32

(2S,4R)-1-[(2S)-2- (2-[4-[4-([[(2R,3S)- 3-[[(2S,11S)-11- Amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)phenyl] butoxy]acetamido) dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- yl)phenyl]methyl] pyrrolidine-2-carboxamide acetate 1007.7 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.61 (s,1H), 7.80 (d, J = 9.4 Hz, 1H), 7.48-7.35 (m, 5H), 7.20-7.09 (m, 5H),7.01 (d, J = 7.4 Hz, 2H), 6.95-6.88 (m, 1H), 6.68 (s, 1H), 5.05 (d, J =9.3 Hz, 1H), 4.56 (d, J = 9.5 Hz, 1H), 4.48-4.34 (m, 5H), 4.28 (d, J =5.7 Hz, 1H), 3.92 (s, 2H), 3.83-3.74 (m, 1H), 3.73-3.56 (m, 1H), 3.51(d, J = 6.6 Hz, 2H), 3.47- 3.39 (m, 2H), 3.38-3.30 (m, 2H), 3.08- 2.97(m, 2H), 2.84 (d, J = 16.1 Hz, 1H), 2.58 (d, J = 7.5 Hz, 2H), 2.55-2.50(m, 2H), 2.43 (s, 3H), 2.12-2.00 (m, 2H), 2.00-1.82 (m, 6H), 1.68-1.48(m, 5H), 1.07 (d, J = 6.1 Hz, 3H), 0.94 (s, 9H). J33

(2S,4S)-1-[(2S)-2-(2- [4-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)phenyl] butoxy]acetamido)- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate 1007.7 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.67 (t, J = 6.1 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.48-7.32 (m,4H), 7.20-7.08 (m, 5H), 7.01 (d, J = 7.4 Hz, 2H), 6.92 (dd, J = 8.1, 6.7Hz, 1H), 6.66 (s, 1H), 5.44 (s, 1H), 5.05 (dd, J = 10.9, 3.2 Hz, 1H),4.52 (d, J = 9.3 Hz, 1H), 4.47-4.36 (m, 4H), 4.34-4.17 (m, 2H),3.94-3.83 (m, 3H), 3.82-3.72 (m, 1H), 3.51-3.26 (m, 9H), 3.05-2.95 (m,2H), 2.85 (dd, J = 16.8, 3.2 Hz, 1H), 2.59 (t, J = 7.4 Hz, 2H), 2.44 (s,3H), 2.40-2.29 (m, 1H), 2.12-1.92 (m, 3H), 1.90 (s, 3H), 1.75 (dt, J =12.3, 6.0 Hz, 1H), 1.63-1.49 (m, 4H), 1.07 (d, J = 6.2 Hz, 3H), 0.95 (s,9H). J34

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamideacetate 977.9 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.48 (d, J = 8.1 Hz, 2H),7.43 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.9 Hz,2H), 7.11-7.06 (m, 2H), 7.05- 7.00 (m, 1H), 5.16 (dd, J = 10.9, 3.7 Hz,1H), 4.61-4.55 (m, 1H), 4.55-4.43 (m, 3H), 4.39-4.32 (m, 1H), 4.04-3.98(m, 1H), 3.90 (t, J = 10.6 Hz, 2H), 3.82 (dd, J = 10.9, 4.0 Hz, 1H),3.65-3.54 (m, 1H), 3.52-3.41 (m, 1H), 3.23-3.14 (m, 2H), 3.06 (d, J =7.3 Hz, 1H), 3.04-2.99 (m, 1H), 2.67-2.60 (m, 2H), 2.48 (s, 3H),2.38-2.15 (m, 6H), 2.10 (ddd, J = 13.3, 9.0, 4.5 Hz, 1H), 2.00 (d, J =8.7 Hz, 1H), 1.95 (s, 3H), 1.76-1.58 (m, 6H), 1.32 (t, J = 7.3 Hz, 1H),1.20 (d, J = 6.4 Hz, 3H), 1.04 (s, 9H). J35

(2S,4S)-1-[(2S)-2-[5- [4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl] pyrrolidine-2- carboxamideacetate [M/2 + 1)]⁺ = 489.6 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.62 (t,J = 6.1 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.45- 7.35 (m, 4H), 7.23-7.16 (m, 3H), 7.15- 7.06 (m, 2H), 7.02 (d, J =7.4 Hz, 2H), 6.93 (dd, J = 8.1, 6.8 Hz, 1H), 6.66 (s, 1H), 5.06 (dd, J =10.9, 3.2 Hz, 1H), 4.50-4.32 (m, 5H), 4.31-4.15 (m, 2H), 3.94 (dd, J =10.2, 5.7 Hz, 1H), 3.78 (q, J = 7.7, 5.2 Hz, 1H), 3.50-3.32 (m, 5H),3.02 (t, J = 5.5 Hz, 2H), 2.86 (dd, J = 16.8, 3.3 Hz, 1H), 2.55 (d, J =7.3 Hz, 2H), 2.45 (s, 3H), 2.37-2.23 (m, 2H), 2.21-1.93 (m, 3H), 1.90(s, 3H), 1.85- 1.69 (m, 2H), 1.63-1.45 (m, 6H), 1.08 (d, J = 6.2 Hz,3H), 0.96-0.92 (m, 9H). J36

(2S,4R)-1-[(2S)-2- [2-[2-(2-[3-[4- ((2R,3S)-3- [[(2S,11S)-11-Amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phen yl]propoxy] ethoxy)ethoxy] acetamido]- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate 1037.7 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.59 (t, J = 6.0 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.46-7.33 (m,5H), 7.21-7.14 (m, 3H), 7.10 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.5 Hz,2H), 6.96-6.88 (m, 1H), 6.67 (s, 1H), 5.05 (dd, J = 10.9, 3.2 Hz, 1H),4.58 (d, J = 9.6 Hz, 1H), 4.48-4.33 (m, 5H), 4.25 (dd, J = 15.7, 5.6 Hz,1H), 3.99 (s, 2H), 3.78 (s, 1H), 3.71-3.59 (m, 4H), 3.54 (t, J = 4.6 Hz,2H), 3.48- 3.28 (m, 6H), 3.03 (d, J = 12.8 Hz, 2H), 2.90-2.80 (m, 1H),2.59 (t, J = 7.7 Hz, 2H), 2.44 (s, 3H), 2.13-2.00 (m, 3H), 1.99-1.92 (m,2H), 1.91 (s, 3H), 1.84-1.70 (m, 3H), 1.62-1.45 (m, 1H), 1.08 (d, J =6.2 Hz, 3H), 0.95 (s, 9H). J37

(2S,4R)-1-[(2S)-2- [2-[2-(2-[3-[4- ([[(2R,3S)-3- [[(2S,11S)-11-Amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)phenyl] propoxy]ethoxy) ethoxylacetamido]-dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol-yl)phenyl]methyl] pyrrolidine-2- carboxamide acetate 1081.8 (400 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.60 (t, J = 6.1 Hz, 1H), 7.80 (d, J = 9.3 Hz,1H), 7.45-7.38 (m, 5H), 7.22-7.08 (m, 4H), 7.02 (d, J = 7.5 Hz, 2H),6.96- 6.90 (m, 1H), 6.67 (s, 1H), 5.06 (dd, J = 11.0, 3.2 Hz, 1H), 4.58(d, J = 9.6 Hz, 1H), 4.48-4.33 (m, 5H), 4.30-4.20 (m, 1H), 3.98 (s, 2H),3.85-3.73 (m, 1H), 3.70-3.56 (m, 6H), 3.50 (t, J = 4.8 Hz, 2H),3.47-3.42 (m, 2H), 3.40-3.25 (m, 9H), 3.04 (d, J = 12.6 Hz, 2H), 2.86(d, J = 15.1 Hz, 1H), 2.58 (t, J = 7.8 Hz, 2H), 2.45 (s, 3H), 2.12-1.90(m, 3H), 1.87 (s, 3H), 1.82-1.70 (m, 2H), 1.63- 1.50 (m, 1H), 1.09 (d, J= 6.2 Hz, 3H), 0.95 (s, 9H). J38

(2S,4R)-1-[(2S)-2- [15-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]-3,6,9,12- tetraoxapenta- decanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate 1125.8 (400 MHz, DMSO-d₆) δ 8.98 (d,J = 3.1 Hz, 1H), 8.60 (s, 1H), 7.85-7.77 (m, 1H), 7.46-7.35 (m, 5H),7.21-7.14 (m, 3H), 7.11 (d, J = 7.8 Hz, 2H), 7.01 (t, J = 5.9 Hz, 2H),6.93 (dd, J = 11.8, 7.6 Hz, 1H), 6.68 (s, 1H), 5.06 (d, J = 11.0 Hz,1H), 4.57 (d, J = 9.4 Hz, 1H), 4.49- 4.34 (m, 5H), 4.30-4.16 (m, 1H),3.96 (d, J = 2.6 Hz, 2H), 3.78 (s, 1H), 3.64- 3.43 (m, 16H), 3.40-3.30(m, 6H), 3.11- 2.96 (m, 2H), 2.85 (d, J = 16.9 Hz, 1H), 2.57 (d, J = 7.8Hz, 2H), 2.44 (s, 3H), 2.12-1.94 (m, 4H), 1.91 (s, 3H), 1.84- 1.68 (m,2H), 1.61-1.47 (m, 1H), 1.08 (dd, J = 6.2, 2.8 Hz, 3H), 0.94 (s, 9H).J39

(3S,6S)-3-Amino-N- ((2R,3S)-6-amino-2- ((4-(4-(((S)-1((2S,4R)-4-hydroxy- 2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1- oxobutan-2- yl)amino)-4-oxobutyl)benzyl)oxy)- 6-oxohexan-3-yl)- 4-oxo-1,2,3,4,6,7-hexahydroazepino[3, 2,1-hi]indole-6- carboxamide acetate [M/2 + 1]⁺ =482.5 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.90(d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.46- 7.35 (m, 4H), 7.19(d, J = 8.1 Hz, 1H), 7.11 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 7.6 Hz, 2H),6.97-6.89 (m, 1H), 6.68 (s, 1H), 5.13 (s, 1H), 5.05 (dd, J = 10.9, 3.3Hz, 1H), 4.57 (d, J = 9.4 Hz, 1H), 4.49- 4.30 (m, 5H), 4.22 (dd, J =15.7, 5.4 Hz, 1H), 3.78 (s, 1H), 3.70-3.61 (m, 2H), 3.47-3.40 (m, 2H),3.40-3.30 (m, 4H), 3.02 (s, 2H), 2.85 (d, J = 15.7 Hz, 1H), 2.68-2.57(m, 2H), 2.45 (s, 3H), 2.28 (q, J = 7.3 Hz, 1H), 2.17 (q, J = 7.2 Hz,1H), 2.05 (s, 2H), 2.12-1.99 (m, 1H), 1.90 (s, 3H), 1.84-1.69 (m, 2H),1.62- 1.45 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H), 0.95 (s, 9H). J40

(2S,4R)-1-[(2S)-2- (2-[2-[4-([[(2R,3S)- 3-[[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)phenyl] ethoxy]acetamido)- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate 979.7 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.61 (t, J = 6.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.48-7.33 (m,5H), 7.20 (s, 4H), 7.15 (s, 1H), 7.05-6.98 (m, 2H), 6.97-6.88 (m, 1H),6.67 (s, 1H), 5.05 (dd, J = 10.8, 3.3 Hz, 1H), 4.55 (d, J = 9.6 Hz, 1H),4.50-4.34 (m, 5H), 4.26 (dd, J = 15.9, 5.6 Hz, 1H), 3.98-3.88 (m, 2H),3.78 (s, 1H), 3.74-3.58 (m, 4H), 3.48-3.31 (m, 4H), 3.03 (d, J = 12.7Hz, 2H), 2.90-2.80 (m, 4H), 2.43 (s, 3H), 2.09-2.03 (m, 3H), 2.01-1.86(m, 1H), 1.90 (s, 3H), 1.79 (s, 1H), 1.59-1.51 (m, 1H), 1.07 (d, J = 6.2Hz, 3H), 0.93 (s, 9H). J41

(2S,4R)-1-[(2S)-2- ([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl] ethoxy]ethoxy) acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate 1023.7 (400 MHz, DMSO-d₆) δ 8.97 (s,1H), 8.59 (t, J = 6.1 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.49-7.35 (m,5H), 7.21-7.15 (m, 4H), 7.02 (d, J = 7.4 Hz, 2H), 6.93 (dd, J = 8.2, 6.7Hz, 1H), 6.67 (s, 1H), 5.06 (dd, J = 10.9, 3.2 Hz, 1H), 4.59 (d, J = 9.6Hz, 1H), 4.51-4.35 (m, 5H), 4.26 (dd, J = 15.8, 5.7 Hz, 1H), 3.98 (s,2H), 3.85-3.78 (m, 1H), 3.73-3.54 (m, 9H), 3.50-3.41 (m, 2H), 3.37 (dd,J = 16.9, 11.1 Hz, 1H), 3.02 (s, 2H), 2.90-2.78 (m, 4H), 2.43 (s, 3H),2.15-2.03 (m, 2H), 2.00-1.93 (m, 2H), 1.91 (s, 3H), 1.84-1.77 (m, 1H),1.58 (dd, J = 15.0, 9.7 Hz, 1H), 1.08 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H).J42

(2S,4R)-1-[(2S)-2- [15-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]-3,6,9,12- tetraoxapenta- decanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 1067.7 (400 MHz, DMSO-d₆) δ 8.98 (d, J = 3.7Hz, 1H), 8.59 (s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.46-7.37 (m, 5H),7.19-7.10 (m, 5H), 7.01 (d, J = 7.3 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H),6.67 (s, 1H), 5.05 (d, J = 11.1 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H),4.49-4.31 (m, 6H), 4.25 (d, J = 15.5 Hz, 1H), 3.97 (s, 2H), 3.78 (s,1H), 3.70-3.49 (m, 13H), 3.48-3.30 (m, 3H), 3.01 (s, 2H), 2.84 (d, J =16.5 Hz, 1H), 2.76 (t, J = 7.4 Hz, 2H), 2.44 (s, 3H), 2.12-1.92 (m, 4H),1.89 (s, 3H), 1.85- 1.71 (m, 1H), 1.62-1.48 (m, 1H), 1.07 (d, J = 6.2Hz, 3H), 0.95 (m, 9H). J43

(2S,4R)-1-[(2S)-2- [14-[4-([[(2R,3S)-3- [[(2S,11S)-11- Amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]-3,6,9,12- tetraoxatetra- decanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide acetate 1111.7 (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.61 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.46-7.38 (m,5H), 7.18 (t, J = 6.6 Hz, 5H), 7.02 (d, J = 7.5 Hz, 2H), 6.93 (dd, J =8.0, 6.8 Hz, 1H), 6.68 (s, 1H), 5.07 (dd, J = 10.9, 3.2 Hz, 1H), 4.58(d, J = 9.6 Hz, 2H), 4.49-4.34 (m, 6H), 4.25 (dd, J = 15.8, 5.6 Hz, 1H),3.97 (s, 2H), 3.84-3.75 (m, 1H), 3.68 (dd, J = 10.7, 3.9 Hz, 1H),3.65-3.50 (m, 16H), 3.44 (dd, J = 12.4, 6.5 Hz, 2H), 3.40-3.33 (m, 1H),3.03 (q, J = 5.9, 5.0 Hz, 2H), 2.85 (dd, J = 16.6, 3.2 Hz, 1H),2.82-2.75 (m, 2H), 2.45 (s, 3H), 2.15-1.97 (m, 4H), 1.92 (td, J = 8.6,4.3 Hz, 2H), 1.79 (ddd, J = 10.0, 6.7, 3.5 Hz, 1H), 1.62-1.51 (m, 1H),1.08 (d, J = 6.3 Hz, 3H), 0.95 (s, 9H). J44

(2S,4R)-1-[(2S)-2- [6-[4-([[(2R,3S)-3- [[(2S,11S)-11- Amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]hexanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide991.3 (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H),7.40-7.33 (m, 4H), 7.27 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H),7.09-6.99 (m, 4H), 6.43 (d, J = 8.8 Hz, 1H), 6.36 (s, 1H), 5.55 (s, 1H),5.14 (dd, J = 9.8, 3.2 Hz, 1H), 4.70 (t, J = 8.0 Hz, 1H), 4.65-4.50 (m,4H), 4.41- 4.31 (m, 2H), 4.11 (d, J = 11.4 Hz, 1H), 3.93 (s, 1H),3.66-3.54 (m, 3H), 3.38- 3.21 (m, 2H), 3.05 (d, J = 6.3 Hz, 2H), 2.61(m, 3H), 2.53 (s, 3H), 2.50-2.44 (m, 1H), 2.23-2.10 (m, 4H), 2.09-1.91(m, 6H), 1.74 (dt, J = 18.2, 6.7 Hz, 1H), 1.66-1.56 (m, 4H), 1.31 (p, J= 7.7, 7.2 Hz, 2H), 1.22 (d, J = 6.3 Hz, 3H), 0.95 (s, 9H). J45

(2S,4R)-1-[(2S)-2- [7-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]heptanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamideacetate 1005.8 (400 MHz, CD₃OD) δ 8.87 (s, 1H), 7.49-7.37 (m, 4H), 7.21(d, J = 7.9 Hz, 2H), 7.14-6.94 (m, 5H), 5.12 (dd, J = 11.0, 3.7 Hz, 1H),4.62 (s, 1H), 4.60- 4.42 (m, 7H), 4.34 (d, J = 15.4 Hz, 2H), 3.98 (d, J= 11.7 Hz, 1H), 3.89 (d, J = 11.2 Hz, 1H), 3.79 (dd, J = 11.0, 3.9 Hz,1H), 3.67 (d, J = 9.6 Hz, 1H), 3.63-3.52 (m, 1H), 3.49-3.37 (m, 2H),3.15 (s, 2H), 3.04-2.94 (m, 1H), 2.59 (t, J = 7.6 Hz, 2H), 2.47 (s, 3H),2.31-1.99 (m, 5H), 1.90 (s, 3H), 1.78-1.53 (m, 5H), 1.44-1.30 (m, 4H),1.18 (d, J = 6.3 Hz, 3H), 1.03 (s, 9H). J46

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[[4-(3-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]methoxy]propyl) phenyl]methoxy] hexanamide acetate794.5 (400 MHz, DMSO-d₆) δ 7.79 (d, J = 9.3 Hz, 1H), 7.20-7.12 (m, 3H),7.10 (t, J = 8.2 Hz, 2H), 7.04-6.95 (m, 4H), 6.95- 6.86 (m, 1H), 6.66(s, 1H), 5.40 (dd, J = 12.9, 5.5 Hz, 1H), 5.05 (dd, J = 10.9, 3.1 Hz,1H), 4.70 (s, 2H), 4.46-4.35 (m, 2H), 3.83-3.72 (m, 1H), 3.59 (s, 3H),3.52-3.39 (m, 4H), 3.35-3.30 (m, 3H), 3.01 (s, 2H), 2.86 (t, J = 16.2Hz, 2H), 2.72 (d, J = 12.7 Hz, 1H), 2.64 (d, J = 14.5 Hz, 1H), 2.59 (d,J = 8.2 Hz, 2H), 2.11-1.91 (m, 4H), 1.90 (s, 3H), 1.87- 1.72 (m, 2H),1.61-1.46 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H). J47

(4S,5R)-4- [[2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[[4-(5-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]propoxy]pentyl) phenyl]methoxy] hexanamide acetate850.7 (400 MHz, DMSO-d₆) δ 7.80 (d, J = 9.2 Hz, 1H), 7.21-7.09 (m, 5H),7.05-6.97 (m, 4H), 6.92 (dd, J = 8.2, 6.6 Hz, 1H), 6.86 (dd, J = 8.1,1.6 Hz, 1H), 6.67 (s, 1H), 5.34 (dd, J = 12.8, 5.3 Hz, 1H), 5.06 (dd, J= 10.9, 3.2 Hz, 1H),4.41 (d, J = 2.4 Hz, 2H), 3.79 (s, 1H), 3.46-3.40(m, 2H), 3.35-3.30 (m, 7H), 3.02 (s, 2H), 2.97-2.80 (m, 2H), 2.78-2.53(m, 8H), 2.13-1.94 (m, 4H), 1.90 (s, 3H), 1.86-1.75 (m, 3H), 1.62-1.50(m, 5H), 1.35 (dt, J = 11.2, 6.6 Hz, 2H), 1.08 (d, J = 6.2 Hz, 3H). J48

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[[4-(5-(3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]propoxy]pentyl) phenyl]methoxy] hexanamide acetate850.6 (400 MHz, DMSO-d₆) δ 7.81 (d, J = 9.3 Hz, 1H), 7.22-7.16 (m, 3H),7.12 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 7.4 Hz, 2H), 7.01-6.89 (m, 3H),6.86 (dd, J = 5.8, 3.1 Hz, 1H), 6.68 (s, 1H), 5.37 (dd, J = 12.6, 5.4Hz, 1H), 5.06 (dd, J = 10.9, 3.2 Hz, 1H), 4.45-4.34 (m, 2H), 3.78 (p, J= 5.4 Hz, 1H), 3.70-3.60 (m, 5H), 3.50-3.40 (m, 7H), 3.03 (q, J = 6.1,5.2 Hz, 2H), 2.98-2.87 (m, 3H), 2.84 (dd, J = 12.3, 4.5 Hz, 1H), 2.72(td, J = 12.9, 4.3 Hz, 1H), 2.66-2.53 (m, 3H), 2.12-2.03 (m, 1H), 1.99(qd, J = 11.9, 10.4, 6.9 Hz, 2H), 1.89 (s, 3H), 1.87-1.73 (m, 3H),1.65-1.50 (m, 5H), 1.35 (h, J = 7.4, 6.3 Hz, 2H), 1.08 (d, J = 6.1 Hz,3H). J49

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} 4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[[4-(2-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]propoxy]ethy) phenyl]methoxy] hexanamide acetate809.5 (400 MHz, DMSO-d₆) δ 7.80 (d, J = 9.2 Hz, 1H), 7.23-7.18 (m, 4H),7.16 (d, J = 9.8 Hz, 1H), 7.01 (d, J = 7.5 Hz, 2H), 6.98-6.88 (m, 3H),6.81 (dd, J = 6.5, 2.4 Hz, 1H), 6.67 (s, 1H), 5.36 (dd, J = 12.5, 5.4Hz, 1H), 5.05 (dd, J = 10.9, 3.2 Hz, 1H), 4.48-4.37 (m, 2H), 3.78 (s,1H), 3.60 (t, J = 6.8 Hz, 2H), 3.57-3.52 (m, 7H), 3.50-3.40 (m, 4H),3.37 (dd, J = 16.8, 10.9 Hz, 1H), 3.03 (d, J = 13.3 Hz, 1H), 2.96-2.85(m, 2H), 2.85-2.78 (m, 2H), 2.73-2.58 (m, 2H), 2.12-1.93 (m, 4H), 1.91(s, 3H), 1.86-1.75 (m, 3H), 1.55 (d, J = 11.7 Hz, 1H), 1.08 (d, J = 6.2Hz, 3H). J50

(4S,5R)-4- [[(2S,11S)-11- Amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[4-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]butyl]phenyl) methoxy]hexanamide 778.4 (400 MHz, CDCl₃) δ 7.34-7.27(m, 2H), 7.16 (dd, J = 7.9, 4.9 Hz, 2H), 7.08 (d, J = 7.0 Hz, 1H),7.05-6.94 (m, 3H), 6.92-6.86 (m, 1H), 6.73-6.66 (m, 1H), 6.49-6.34 (m,1H), 5.52-5.35 (m, 1H), 5.19 (td, J = 10.0, 9.6, 4.3 Hz, 1H), 4.62 (d, J= 11.5 Hz, 1H), 4.41 (dd, J = 11.5, 8.4 Hz, 1H), 3.96 (d, J = 10.6 Hz,1H), 3.67-3.57 (m, 2H), 3.53-3.48 (m, 3H), 3.37-3.26 (m, 2H), 3.08 (d, J= 8.0 Hz, 2H), 2.98-2.86 (m, 3H), 2.85-2.74 (m, 2H), 2.70 (q, J = 7.0Hz, 2H), 2.27-1.95 (m, 7H), 1.84-1.62 (m, 4H), 1.23 (dd, J = 6.4, 2.0Hz, 3H). J51

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[5-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-4-yl]pentyl]phenyl) methoxy] hexanamide acetate 792.7 (400 MHz, DMSO-d₆) δ7.80 (d, J = 9.3 Hz, 1H), 7.21-7.15 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H),7.02 (d, J = 7.5 Hz, 2H), 6.98-6.82 (m, 4H), 6.67 (s, 1H), 5.36 (dd, J =12.5, 5.3 Hz, 1H), 5.06 (dd, J = 11.0, 3.2 Hz, 1H), 4.47-4.36 (m, 2H),3.78 (s, 1H), 3.43 (dd, J = 12.7, 7.4 Hz, 2H), 3.39-3.32 (m, 6H), 3.02(s, 2H), 2.95-2.80 (m, 4H), 2.70-2.65 (m, 1H), 2.62-2.54 (m, 2H),2.12-1.90 (m, 4H), 1.91 (s, 3H), 1.85-1.75 (m, 1H), 1.67- 1.52 (m, 5H),1.46-1.37 (m, 2H), 1.08 (d, J = 6.2 Hz, 3H). J52

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-([5-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]pentyl]oxy)propyl] phenyl]methoxy) hexanamideacetate 850.7 (400 MHz, DMSO-d₆) δ 7.79 (d, J = 9.3 Hz, 1H), 7.22-7.08(m, 5H), 7.05-7.00 (m, 4H), 6.96-6.83 (m, 2H), 6.67 (s, 1H), 5.33 (dd, J= 12.9, 5.2 Hz, 1H), 5.09-5.01 (m, 1H), 4.41 (d, J = 2.4 Hz, 2H), 3.79(s, 1H), 3.50-3.38 (m, 1H), 3.35-3.30 (m, 13H), 3.01 (s, 2H), 2.86 (t, J= 13.9 Hz, 2H), 2.70-2.55 (m, 4H), 2.12-1.95 (m, 3H), 1.87 (s, 3H),1.85- 1.75 (m, 3H), 1.65-1.50 (m, 5H), 1.36 (s, 2H), 1.08 (d, J = 6.2Hz, 3H). J53

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-([4-[3-([5-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-4- yl]pentyl]oxy)propyl] phenyl]methoxy) hexanamideacetate 850.6 (400 MHz, DMSO-d₆) δ 7.79 (d, J = 9.1 Hz, 1H), 7.19 (d, J= 7.9 Hz, 2H), 7.15 (s, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 7.5Hz, 2H), 6.99-6.88 (m, 3H), 6.87 (dd, J = 5.5, 3.4 Hz, 1H), 6.66 (s,1H), 5.36 (dd, J = 12.6, 5.3 Hz, 1H), 5.06 (dd, J = 10.7, 3.1 Hz, 1H),4.47- 4.36 (m, 2H), 3.79 (s, 1H), 3.56 (s, 3H), 3.48-3.42 (m, 2H),3.36-3.30 (m, 6H), 3.02 (s, 2H), 2.95-2.86 (m, 4H), 2.75- 2.56 (m, 4H),2.06-1.93 (m, 4H), 1.91 (s, 3H), 1.82-1.74 (m, 3H), 1.68-1.55 (m, 5H),1.45 (d, J = 7.5 Hz, 2H), 1.09 (d, J = 6.2 Hz, 3H). J54

(2S,4R)-N-[(2-[4-[4- ([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]butoxy]- 4-(4- methyl-1,3-thiazol- yl)phenyl)methyl]-1-[(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3- dimethylbutanoyl]- 4-hydroxypyrrolidine- 2-carboxamide 1051.7 Used directly in next stepwithout further purification J55

(2S,4R)-N-[[2-([5- [4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]pentyl] oxy)-4-(4- methyl-1,3-thiazol- yl)phenyl]methyl]-1-[(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3- dimethylbutanoyl]- 4-hydroxypyrrolidine- 2-carboxamide acetate [(M + 18)]⁺ = 1083.5 (400 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 9.3 Hz,1H), 7.41 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 9.2, 2.8 Hz, 1H), 7.22-7.11(m, 5H), 7.04-6.98 (m, 3H), 6.95 (dd, J = 7.7, 1.6 Hz, 1H), 6.95-6.87(m, 1H), 6.66 (s, 1H), 5.05 (dd, J = 10.9, 3.2 Hz, 1H), 4.61 (d, J = 9.2Hz, 1H), 4.53 (t, J = 8.2 Hz, 1H), 4.46-4.39 (m, 2H), 4.36 (s, 1H), 4.30(dd, J = 16.5, 6.0 Hz, 1H), 4.20 (dd, J = 16.6, 5.5 Hz, 1H), 4.05 (t, J= 6.3 Hz, 2H), 3.78-3.70 (m, 1H), 3.71-3.57 (m, 2H), 3.48-3.31 (m, 4H),3.01 (s, 2H), 2.85 (dd, J = 16.6, 3.2 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H),2.46 (s, 3H), 2.12-2.01 (m, 2H), 1.99-1.90 (m, 2H), 1.90 (s, 3H),1.86-1.76 (m, 3H), 1.75-1.70 (m, 2H), 1.69-1.53 (m, 2H), 1.50 (d, J =7.2 Hz, 2H), 1.43-1.31 (m, 2H), 1.23 (dd, J = 8.6, 3.4 Hz, 2H), 1.08 (d,J = 6.2 Hz, 3H), 0.97 (s, 9H). J56

(2S,4R)-N-[(2-[2-[2- (2-[3-[4-([[(2R,3S)- 3-[[(2S,11S)-11-amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]propoxy]ethoxy) ethoxylethoxyl-4-(4- methyl-1,3-thiazol-yl)phenyl)methyl]- 1-[(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]- 4- hydroxypyrrolidine- 2-carboxamide acetate [(M/2 +1]⁺ = 585.7 (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.48 (d, J = 6.2 Hz, 1H),7.80 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.9 Hz,1H), 7.23-7.14 (m, 3H), 7.11 (d, J = 7.9Hz, 2H), 7.06-6.99 (m, 3H),6.99-6.93 (m, 1H), 6.92 (dd, J = 8.3, 6.6 Hz, 1H), 6.67 (s, 1H), 5.05(dd, J = 10.9, 3.2 Hz, 1H), 4.60 (d, J = 9.1 Hz, 1H), 4.52 (t, J = 8.3Hz, 1H), 4.41 (s, 2H), 4.36 (s, 1H), 4.30 (d, J = 6.2 Hz, 1H), 4.25-4.15(m, 3H), 3.85-3.75 (m, 3H), 3.70-3.62 (m, 3H), 3.60-3.51 (m, 4H),3.50-3.40 (m, 3H), 3.41-3.30 (m, 5H), 3.02 (s, 2H), 2.85 (d, J = 15.4Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.12-2.05 (m, 2H),2.03-1.93 (m, 4H), 1.90 (s, 3H), 1.81-1.72 (m, 3H), 1.60-1.50 (m, 1H),1.45-1.34 (m, 2H), 1.23 (d, J = 8.6 Hz, 2H), 1.08 (d, J = 6.2 Hz, 3H),0.96 (s, 9H). J57

(2S,4R)-N-[[2-([15- [4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]-3,6,9,12- tetraoxapentadecan- 1-yl]oxy)-4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl]- 1-[(2S)-2-[(1-fluorocyclopropyl) formamido]-3,3- dimethylbutanoyl]-hydroxypyrrolidine- 2-carboxamide acetate 1213.9 (400 MHz, DMSO-d₆) δ8.98 (s, 1H), 7.80 (d, J = 9.2 Hz, 1H),7.41 (d, J = 7.9 Hz, 1H), 7.29(d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H),7.06-6.88 (m, 5H), 6.67 (s, 1H), 5.17 (s, 1H), 5.09-5.02 (m, 1H), 4.60(d, J = 9.0 Hz, 1H), 4.52 (t, J = 8.0 Hz, 1H), 4.41 (s, 2H), 4.36 (s,1H), 4.30 (s, 1H), 4.25-4.15 (m, 3H), 3.85-3.76 (m, 3H), 3.66-3.60 (m,3H), 3.58-3.54 (m, 2H), 3.54-3.50 (m, 6H), 3.49-3.41 (m, 4H), 3.40-3.30(m, 8H), 3.02 (s, 2H), 2.85 (d, J = 17.0 Hz, 1H), 2.59 (t, J = 7.7 Hz,2H), 2.46 (s, 3H), 2.08 (d, J = 10.3 Hz, 2H), 1.91 (s, 3H), 1.81-1.73(m, 3H), 1.37 (d, J = 7.9 Hz, 2H), 1.22 (d, J = 4.5 Hz, 2H), 1.08 (d, J= 6.2 Hz, 3H), 0.96 (s, 9H). J58

(2S,4R)-N-[[2-([18- [4-([[(2R,3S)-3- [(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]-3,6,9,12,15- pentaoxaoctadecan- 1-yl]oxy)-4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl]- 1-[(2S)-2-[(1-fluorocyclopropyl) formamido]-3,3- dimethylbutanoyl]-hydroxypyrrolidine- 2-carboxamide acetate N/A (400 MHz, DMSO-d₆) δ 8.98(s, 1H), 8.47 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.41 (d, J= 7.8 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.23-7.09 (m, 5H), 7.08-6.99(m, 3H), 6.97 (dd, J = 7.8, 1.7 Hz, 1H), 6.92 (dd, J = 8.2, 6.7 Hz, 1H),6.66 (s, 1H), 5.05 (dd, J = 10.8, 3.2 Hz, 1H), 4.60 (d, J = 9.3 Hz, 1H),4.52 (t, J = 8.2 Hz, 1H), 4.41 (d, J = 2.8 Hz, 2H), 4.38-4.26 (m, 2H),4.26-4.15 (m, 3H), 3.79 (m, 3H), 3.70-3.59 (m, 3H), 3.58- 3.31 (m, 22H),3.02 (s, 2H), 2.90-2.81 (m, 1H), 2.59 (t, J = 7.7 Hz, 2H), 2.46 (s, 3H),2.14-1.99 (m, 2H), 1.96 (m, 2H), 1.90 (s, 3H), 1.77 (m, 3H), 1.55 (d, J= 10.6 Hz, 1H), 1.43-1.31 (m, 2H), 1.26-1.19 (m, 2H), 1.08 (d, J = 6.2Hz, 3H), 0.96 (s, 9H). J59

(2S,4R)-N-[(2-[3-[4- ([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]propoxy]-4-(4- methyl-1,3-thiazol- 5- yl)phenyl)methyl]-1-[(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3- dimethylbutanoyl]-hydroxypyrrolidine- 2-carboxamide acetate 1037.3 (400 MHz, DMSO-d₆) δ8.98 (s, 1H), 8.52 (t, J = 6.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.43(d, J = 7.7 Hz, 1H), 7.33- 7.26 (m, 1H), 7.25-7.15 (m, 5H), 7.03- 6.93(m, 4H), 6.89 (dd, J = 8.1, 6.7 Hz, 1H), 6.67 (s, 1H), 5.16 (s, 1H),5.05 (dd, J = 11.0, 3.2 Hz, 1H), 4.61 (d, J = 9.2 Hz, 1H), 4.53 (t, J =8.2 Hz, 1H), 4.42 (s, 2H), 4.35-4.25 (m, 2H), 4.06 (t, J = 6.1 Hz, 2H),3.79 (s, 1H), 3.70-3.57 (m, 2H), 3.44 (dd, J = 9.1, 3.3 Hz, 2H),3.36-3.30 (m, 4H), 3.05-2.98 (m, 2H), 2.89-2.80 (m, 1H), 2.78 (t, J =7.6 Hz, 2H), 2.45 (s, 3H), 2.14-1.95 (m, 5H), 1.90 (s, 3H), 1.81-1.74(m, 1H), 1.55 (d, J = 10.7 Hz, 1H), 1.43-1.29 (m, 2H), 1.22 (dd, J =8.2, 3.4 Hz, 2H), 1.08 (d, J = 6.2 Hz, 3H), 0.97 (s, 9H). J60

(2S,4R)-N-[[2-(2-[3- [4-([[(2R,3S)-3- [[(2S,11S)-11- Amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)phenyl] propoxy]ethoxy)- 4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl]- 1-[(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]- 4- hydroxypyrrolidine- 2-carboxamide 1081.7 (400 MHz,CDCl₃) δ 8.70 (s, 1H), 7.39 (d, J = 6.5 Hz, 1H), 7.36 (d, J = 7.7 Hz,1H), 7.25 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 7.12-7.05 (m,2H), 7.03- 6.97 (m, 3H), 6.93 (d, J = 1.7 Hz, 1H), 6.36 (s, 1H), 5.34(s, 1H), 5.27-5.17 (m, 1H), 4.66 (t, J = 7.9 Hz, 1H), 4.62-4.54 (m, 2H),4.48 (s, 1H), 4.43 (m, 3H), 4.22 (dq, J = 9.2, 4.8, 3.7 Hz, 2H), 3.98(d, J = 10.6 Hz, 1H), 3.94-3.79 (m, 3H), 3.71-3.54 (m, 5H), 3.40-3.26(m, 2H), 3.08 (t, J = 6.9 Hz, 2H), 2.73 (m, 2H), 2.55 (s, 3H), 2.34(ddd, J = 12.8, 7.8, 4.7 Hz, 1H), 2.14-2.02 (m, 5H), 1.96 (m, 2H), 1.81(dd, J = 12.5, 7.1 Hz, 1H), 1.36-1.31 (m, 2H), 1.29 (d, J = 6.2 Hz, 2H),1.24 (d, J = 6.3 Hz, 3H), 0.97 (s, 9H). J61

(2S,4R)-N-([2-[2-(2- [3-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]propoxy] ethoxy) ethoxy]-4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl)- 1-[(2S)-2-[(1- fluorocyclopropyl) formamido]-3,3-dimethylbutanoyl]- 4- hydroxypyrrolidine- 2-carboxamide acetate 1125.8(400 MHz, DMSO-d₆) 8.98 (d, J = 4.2 Hz, 1H), 8.48 (s, 1H), 7.80 (d, J =9.4 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.18(s, 1H), 7.16 (s, 2H), 7.10 (d, J = 7 .8 Hz, 2H), 7.07- 6.87 (m, 4H),6.67 (s, 1H), 5.05 (d, J = 10.2 Hz, 1H), 4.60 (d, J = 9.0 Hz, 1H), 4.51(t, J = 8.4 Hz, 1H), 4.42-4.38 (m, 2H), 4.32 (d, J = 15.8 Hz, 2H),4.25-4.15 (m, 2H), 3.85-3.73 (m, 3H), 3.69-3.56 (m, 3H), 3.55-3.48 (m,1H), 3.45-3.30 (m, 6H), 3.05-2.96 (m, 2H), 2.84 (d, J = 16.1 Hz, 1H),2.63-2.53 (m, 3H), 2.52- 2.41 (m, 5H), 2.12-2.00 (m, 3H), 2.00- 1.92 (m,2H), 1.90 (s, 3H), 1.83-1.70 (m, 3H), 1.61-1.46 (m, 1H), 1.35 (d, J =16.1 Hz, 2H), 1.22 (d, J = 9.3 Hz, 2H), 1.07 (d, J = 6.2 Hz, 3H), 0.95(s, 9H). J62

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[(4-[4-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]butyl]phenyl) methoxy]hexanamide; acetic acid 778.4 (400 MHz,DMSO-d₆) δ 7.80 (d, J = 9.3 Hz, 1H), 7.22-7.08 (m, 4H), 7.05-6.96 (m,3H), 6.90-6.80 (m, 2H), 6.68 (s, 1H), 5.33 (dd, J = 13.1, 5.3 Hz, 1H),5.12- 5.01 (m, 1H), 4.41 (s, 2H), 3.79 (s, 2 H), 3.59-3.35 (m, 7H), 3.01(s, 2H), 2.90- 2.80 (m, 2H), 2.75-2.55 (m, 5H), 2.13- 1.72 (m, 9H),1.68-1.48 (m, 4H), 1.08 (d, J = 6.3 H, 3H). J63

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien- 2-yl]formamido]-5-[(4-[6-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]hexyl]phenyl) methoxy]hexanamide; acetic acid 806.5 (400 MHz,DMSO-d₆) δ 7.81 (d, J = 9.3 Hz, 1H), 7.21-7.07 (m, 4H), 7.04-6.97 (m,3H), 6.94-6.82 (m, 2H), 6.68 (s, 1H), 5.33 (dd, J = 12.7, 5.3 Hz, 1H),5.05 (dd, J = 11.0, 3.2 Hz, 1H), 4.40 (d, J = 2.3 Hz, 2H), 3.90-3.74 (m,1H), 3.45- 3.32 (m, 11H), 3.01 (dt, J = 9.8, 5.2 Hz, 2H), 2.93-2.79 (m,2H), 2.76-2.66 (m, 1H), 2.59 (m, 3H), 2.17-1.92 (m, 4H), 1.88 (s, 3H),1.78 (ddd, J = 10.4, 6.8, 3.4 Hz, 1H), 1.56 (q, J = 10.9 Hz, 4H),1.41-1.25 (m, 3H), 1.07 (d, J = 6.2 Hz, 3H). J64

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- (methylcarbamoyl) pentan-2-yl]oxy]methyl) phenyl]pentanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide; acetic acid 991.8 (400 MHz, DMSO-d₆) δ 8.99(s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.89 (d, J = 9.4 Hz, 1H), 7.84 (d, J= 9.3 Hz, 1H), 7.61- 7.54 (m, 1H), 7.41 (q, J = 8.4 Hz, 4H), 7.18 (d, J= 8.0 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 7.5 Hz, 2H),6.97-6.85 (m, 2H), 5.05 (dd, J = 11.0, 3.3 Hz, 1H), 4.55 (d, J = 9.4 Hz,1H), 4.49- 4.32 (m, 5H), 4.22 (dd, J = 15.8, 5.1 Hz, 1H), 3.81-3.65 (m,2H), 3.69-3.59 (m, 4H), 3.60 (dq, J = 4.1, 1.5 Hz, 1H), 3.53- 3.32 (m,3H), 3.03 (s, 2H), 2.92-2.79 (m, 1H), 2.60-2.50 (m, 5H), 2.45 (s, 3H),2.32 (s, 1H), 2.19 (s, 1H), 2.08-2.00 (m, 1H), 1.89 (s, 3H), 1.81-1.73(m, 3H), 1.59-1.48 (m, 5H), 1.08 (d, J = 6.1 Hz, 3H), 0.94 (s, 9H). J65

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide; acetic acid 991.4 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 7.83 (dd, J = 9.3, 3.8 Hz, 2H), 7.44 (d, J = 8.3Hz, 2H), 7.45-7.29 (m, 2H), 7.18 (d, J = 7.8 Hz, 3H), 7.11 (d, J = 7.9Hz, 2H), 7.02 (d, J = 7.4 Hz, 2H), 6.98-6.89 (m, 1H), 6.69 (s, 1H),5.10-5.02 (m, 1H), 4.92 (p, J = 6.9 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H),4.47-4.39 (m, 3H), 4.28 (d, J = 4.0 Hz, 1H), 3.79 (m, 1H), 3.66-3.56 (m,2H), 3.49-3.35 (m, 2H), 3.34-3.30 (m, 5H), 3.03 (s, 2H), 2.90-2.81 (m,1H), 2.56 (s, 2H), 2.46 (s, 3H), 2.30 (d, J = 6.3 Hz, 1H), 2.20-1.98 (m,3H), 1.91 (s, 3H), 1.79 (ddd, J = 13.0, 6.8, 3.4 Hz, 2H), 1.70-1.43 (m,7H), 1.41-1.34 (m, 3H), 1.08 (d, J = 6.2 Hz, 3H), 0.94 (s, 9H). J66

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]cyclopropyl] pyrrolidine-2-carboxamide; acetic acid 1004.3 (400 MHz, CD₃OD) δ 8.87 (s, 1H), 7.45-7.30 (m, 4H), 7.23 (d, J = 7.7 Hz, 2H), 7.17-7.08 (m, 3H), 7.05 (dd, J =13.7, 6.5 Hz, 2H), 5.51 (d, J = 1.7 Hz, 1H), 5.21-5.13 (m, 1H), 4.64 (s,1H), 4.57 (q, J = 7.9 Hz, 1H), 4.54-4.45 (m, 3H), 4.07-4.00 (m, 2H),3.91 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 11.1, 3.8 Hz, 1H), 3.62-3.55(m, 1H), 3.52-3.45 (m, 1H), 3.22 (t, J = 6.5 Hz, 2H), 3.08-2.99 (m, 1H),2.64 (d, J = 6.9 Hz, 2H), 2.47 (s, 3H), 2.41-2.27 (m, 5H), 2.30-2.22 (m,1H), 2.24-2.17 (m, 1H), 2.12-2.00 (m, 1H), 1.96 (s, 3H), 1.80-1.60 (m,4H), 1.41-1.25 (m, 5H), 1.20 (d, J = 6.2 Hz, 3H), 1.05 (s, 9H). J67

(2S,4R)-1-[(2S)-2- [6-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]hex- 5-ynamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide;acetic acid 987.3 (400 MHz, DMSO-d₆) δ 8.99 (d, J = 1.8 Hz, 1H), 8.58(t, J = 6.1 Hz, 1H), 7.98 (d, J = 9.6 Hz, 1H), 7.83 (d, J = 9.5 Hz, 1H),7.47-7.28 (m, 7H), 7.26 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H), 7.02 (d, J =5.7 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 6.69 (s, 1H), 5.77 (d, J = 1.8Hz, 1H), 5.06 (d, J = 11.2 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 4.46 (m,3H), 4.44 (d, J = 7.9 Hz, 1H), 4.37 (s, 1H), 4.23 (dd, J = 15.8, 5.4 Hz,1H), 3.80 (s, 1H), 3.68 (s, 2H), 3.37 (dd, J = 16.6, 11.0 Hz, 1H), 3.03(s, 2H), 2.87-2.78 (m, 1H), 2.44 (d, J = 11.4 Hz, 6H), 2.31 (dd, J =15.0, 7.5 Hz, 1H), 2.08 (s, 3H), 2.06-1.92 (m, 5H), 1.91 (s, 3H),1.82-1.75 (m, 3H), 1.57 (s, 1H), 1.09 (d, J = 6.3 Hz, 3H), 0.96 (s, 9H).J68

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]pent- 4-ynamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide[M/2 + 1]⁺= 487.5 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.61 (t, J = 6.0Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.91-7.83 (m, 1H), 7.45-7.21 (m, 8H),7.10-6.94 (m, 2H), 6.75 (s, 1H), 4.60 (d, J = 9.3 Hz, 1H), 4.50-4.33 (m,4H), 4.22 (dd, J = 15.8, 5.3 Hz, 1H), 3.84-3.62 (m, 2H), 3.45 (s, 1H),2.88-2.33 (m, 5H), 2.46 (s, 3H), 2.20-1.50 (m, 1 4H), 1.10 (t, J = 6.5Hz, 3H), 0.95 (s, 9H). J69

(4S,5R)-4- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5-[3-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]propoxy] hexanamide; acetic acid 674.5 (400 MHz, CD₃OD) δ 7.11-6.93(m, 6H), 5.16 (d, J = 7.0 Hz, 1H), 3.96 (s, 1H), 3.55-3.38 (m, 5H), 3.19(d, J = 7.6 Hz, 2H), 2.97-2.88 (m, 1H), 2.85-2.71 (m, 4H), 2.36-2.20 (m,8H), 2.15-2.00 (m, 1H), 1.94 (s, 3H), 1.93-1.80 (m, 4H), 1.70 (s, 1H),1.17 (d, J = 6.3 Hz, 3H). J70

(2S,4R)-1-[(2S)-2- [5-[3-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl] pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide;acetic acid 977.4 (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.48 (d, J = 8.4 Hz,2H), 7.47-7.40 (m, 2H), 7.26-7.14 (m, 2H), 7.16-6.99 (m, 5H), 5.16 (dd,J = 11.0, 3.7 Hz, 1H), 4.65 (s, 1H), 4.62-4.46 (m, 4H), 4.37 (d, J =15.5 Hz, 1H), 4.06-3.98 (m, 1H), 3.98- 3.88 (m, 2H), 3.82 (dd, J = 11.0,3.9 Hz, 1H), 3.63-3.53 (m, 1H), 3.48 (dd, J = 16.7, 10.8 Hz, 1H), 3.37(s, 2H), 3.21 (s, 2H), 3.11-2.97 (m, 2H), 2.62 (s, 2H), 2.49 (s, 3H),2.38-2.18 (m, 4H), 2.15- 1.99 (m, 2H), 1.96 (s, 3H), 1.70-1.65 (m, 5H),1.32 (t, J = 7.3 Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H), 1.04 (s, 9H). J71

(2S,4R)-1-[(2S)-2- [6-[2-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)phen yl]hexanamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide; acetic acid 991.3 (400 MHz, DMSO-d₆) δ 8.99(s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.82 (d, J= 9.2 Hz, 1H), 7.40 (q, J = 8.3 Hz, 4H), 7.24 (t, J = 6.4 Hz, 1H), 7.18(dd, J = 8.6, 7.0 Hz, 2H), 7.1 7-7.07 (m, 1H), 7.01 (d, J = 7.4 Hz, 2H),6.96-6.85 (m, 1H), 6.71 (s, 1H), 5.05 (dd, J = 11.0, 3.3 Hz, 1H),4.58-4.50 (m, 1H), 4.50-4.42 (m, 1H), 4.45-4.37 (m, 2H), 4.35 (s, 1H),4.22 (dd, J = 15.8, 5.4 Hz, 1H), 3.78 (s, 1H), 3.66 (s, 1H), 3.52-3.30(m, 6H), 3.01 (s, 2H), 2.84 (d, J = 16.4 Hz, 1H), 2.56 (d, J = 7.7 Hz,2H), 2.53 (s, 2H), 2.45 (s, 3H), 2.27 (dt, J = 14.7, 7.5 Hz, 1H),2.15-1.90 (m, 5H), 1.89 (s, 3H), 1.56-1.46 (m, 4H), 1.38- 1.22 (m, 4H),1.08 (d, J = 6.7 Hz, 3H), 0.93 (s, 9H). J72

(2R,4S)-1-[(2R)-2- [3-[6-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)naphthalen-2- yl]propanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide; acetic acid 999.7 (400 MHz, CD₃OD) δ 8.89(s, 1H), 7.75 (m, 3H), 7.69 (s, 1H), 7.51-7.36 (m, 6H), 7.07 (d, J = 7.5Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 5.12 (dd, J= 11.0, 3.6 Hz, 1H), 4.76-4.51 (m, 5H), 4.50 (s, 1H), 4.35 (d, J = 1 5.5Hz, 1H), 4.03 (dd, J = 9.7, 5.5 Hz, 1H), 3.95-3.80 (m, 2H), 3.77 (dd, J= 10.9, 4.0 Hz, 1H), 3.64 (dd, J = 6.4, 4.5 Hz, 1H), 3.19 (d, J = 5.9Hz, 2H), 3.15- 3.06 (m, 2H), 3.09-2.99 (m, 1H), 2.93- 2.83 (m, 1H),2.82-2.62 (m, 2H), 2.48 (s, 3H), 2.40-2.22 (m, 3H), 2.20 (d, J = 8.8 Hz,1H), 2.07 (ddd, J = 13.2, 8.9, 4.5 Hz, 1H), 1.95 (s, 3H), 1.36-1.24 (m,2H), 1.80-1.70 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H), 0.91 (s, 9H). J82

(2S,4R)-1-[(2S)-2- [3-[7-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)naphthalen-2- yl]propanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 999.50 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.57 (d, J = 6.1 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.84 (d, J =9.2 Hz, 1H), 7.80 (dd, J = 8.5, 4.4 Hz, 2H), 7.71 (s, 1H), 7.65 (s, 1H),7.46-7.33 (m, 6H), 7.17 (s, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.97-6.86 (m,2H), 6.69 (s, 1H), 5.05 (dd, J = 11.0, 3.3 Hz, 1H), 4.67-4.52 (m, 3H),4.50-4.46 (m, 3H), 4.37-4.35 (m, 1H), 4.24-4.21 (m, 1H), 3.83-3.81 (m,1H), 3.68-3.66 (m, 2H), 3.53-3.43 (m, 2H), 3.35-3.33 (m, 1H), 3.07-2.87(m, 2H), 2.83-2.78 (m, 1H), 2.77-2.67 (m, 2H), 2.58-2.51 (m, 1H), 2.44(s, 3H), 2.14-1.99 (m, 2H), 1.94-1.92 (m, 2H), 1.91-1.88 (m, 5H),1.61-1.59 (m, 1H), 1.12 (d, J = 6.3 Hz, 3H), 0.88 (s, 9H) J83

(2S,4R)-1-[(2S)-2- [4-[6-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-4,azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)naphthalen-2- yl]butanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide1013.75 ¹H NMR (400 MHz, CD₃OD) δ 8.91 (s, 1H), 7.79-7.71 (m, 3H), 7.68(d, J = 8.7 Hz, 1H), 7.52-7.35 (m, 6H), 7.09 (d, J = 7.8 Hz, 1H), 6.99(t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 5.14 (dd, J = 11.0, 3.6Hz, 1H), 4.74-4.66 (m, 2H), 4.62-4.50 (m, 3H), 4.36 (d, J = 15.5 Hz,1H), 4.18 (d, J = 10.8 Hz, 1H), 4.05 (d, J = 11.7 Hz, 1H), 3.95 (d, J =10.9 Hz, 1H), 3.83 (dd, J = 11.0, 3.9 Hz, 1H), 3.64 (dd, J = 6.3, 4.5Hz, 1H), 3.24 (d, J = 6.7 Hz, 2H), 2.90-2.78 (m, 3H), 2.48 (s, 3H), 2.43(s, 0H), 2.41-2.31 (m, 3H), 2.29-2.20 (m, 2H), 2.04 (dd, J = 14.9, 7.6Hz, 3H), 1.75(s, 1H), 1.25 (d, J = 6.3 Hz, 3H), 1.06 (s, 9H) J84

(2S,4R)-1-[(2S)-2- [3-[6-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)naphthalen-1- yl]propanamido]- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide 999.30 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s,1H), 8.58 (t, J = 6.1 Hz, 1H), 8.07 (d, J = 9.4 Hz, 1H), 8.01 (d, J =8.8 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.72(d, J = 8.0 Hz, 1H), 7.46-7.39 (m, 7H), 7.19 (s, 1H), 7.01 (d, J = 7.1Hz, 1H), 6.97-6.87 (m, 2H), 6.71 (s, 1H), 5.18 (s, 1H), 5.06 (d, J = 9.5Hz, 1H), 4.66-4.55 (m, 3H), 4.50- 4.34 (m, 3H), 4.23 (dd, J = 15.6, 5.1Hz, 1H), 3.85 (s, 1H), 3.70 (s, 2H), 3.59- 3.41 (m, 2H), 3.34-3.30 (m,6H), 3.04 (d, J = 12.5 Hz, 2H), 2.82 (d, J = 17.0 Hz, 1H), 2.69 (t, J =7.0 Hz, 1H), 2.51- 2.49 (m, 2H), 2.45 (s, 3H), 2.10-2.06 (m, 2H),2.00-1.88 (m, 2H), 1.83-1.79 (m, 1H), 1.59-1.57 (m, 1H), 1.13 (d, J =6.3 Hz, 3H), 0.94 (s, 9H). J85

(2S,4R)-1-[(2S)-2- [4-[6-([[(2S,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)naphthalen-1- yl]butanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- yl)phenyl]methyl] pyrrolidine-2- carboxamide 1013.20¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.00(dd, J = 13.5, 9.1 Hz, 2H), 7.91-7.77 (m, 3H), 7.71 (d, J = 8.2 Hz, 1H),7.52-7.29 (m, 6H), 7.18 (s, 1H), 7.01 (dd, J = 6.8, 2.3 Hz, 1H),6.96-6.84 (m, 2H), 6.70 (s, 1H), 5.05 (dd, J = 11.0, 3.2 Hz, 1H),4.64-4.59 (m, 3H), 4.46-4.42 (m, 2H), 4.37-4.35 (m, 1H), 4.24-4.15 (m,1H), 3.89-3.79 (m, 2H), 3.69 (d, J = 3.2 Hz, 2H), 3.54-3.49 (m, 1H),3.37-3.62 (m, 1H), 3.03-2.98 (m, 2H), 2.86-2.66 m, 3H), 2.45 (s, 3H),2.42-2.24 (m, 2H), 2.18-2.00 (m, 2H), 1.92-1.88 (m, 10H), 1.62-1.60 (m,1H), 1.20-1.03 (m, 3H), 0.96 (s, 9H). J86

(2S,4R)-1-[(2S)-2- [(5E)-6-[4- ([[(2R,3S)-3- [[(2S,11S)-11-amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )} 4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]hex-5- enamido]- 3,3 dimethylbutanoyl]-4- hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide989.65 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.60 (t, J = 6.0 Hz,1H), 8.28 (s, 1H), 7.94-7.90 (m, 2H), 7.41 (q, J = 8.2 Hz, 5H), 7.32 (d,J = 8.0 Hz, 2H), 7.21 (d, J = 8.1 Hz, 3H), 7.03 (d, J = 7.5 Hz, 2H),6.95 (dd, J = 8.2, 6.5 Hz, 1H), 6.72 (s, 1H), 6.38 (d, J = 15.9 Hz, 1H),6.34-6.23 (m, 1H), 5.07 (dd, J = 11.2, 3.2 Hz, 1H), 4.57 (d, J = 9.3 Hz,1H), 4.49- 4.39 (m, 4H), 4.37 (s, 1H), 4.22 (dd, J = 15.9, 5.3 Hz, 1H),3.81-3.75 (m, 2H), 3.70-3.66 (m, 2H), 3.47-3.36 (m, 6H), 3.08-3.05 (m,2H), 2.82 (d, J = 16.6 Hz, 1H), 2.45 (s, 3H), 2.37-2.33 (m, 1H),2.24-2.14 (m, 3H), 2.12-1.97 (m, 3H), 1.94-1.87 (m, 1H), 1.84-1.72 (m,1H), 1.70-1.62 (m, 1H), 1.58-1.52 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H),0.95 (s, 9H). J87

(2S,4R)-1-[(2S)-2- [(4E)-5-[4- ([[(2R,3S)-3- [[(2S,11S)-11-amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-yl]formamido]-5- 4(13),5,7-trien-2- carbamoylpentan-2- yl]oxy]methyl)phenyl]pent-4- enamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide975.4 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 5.8 Hz,1H), 7.97 (d, J = 9.9 Hz, 1H), 7.85-7.81 (m, 1H), 7.41 (q, J = 8.2 Hz,4H), 7.28 (d, J = 7.9 Hz, 2H), 7.23-7.15 (m, 3H), 7.02 (d, J = 7.0 Hz,2H), 6.94 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 6.41 (d, J = 15.8 Hz, 1H),6.31-6.21 (m, 1H), 5.14 (d, J = 3.5 Hz, 1H), 5.05 (d, J = 10.9 Hz, 1H),4.58 (d, J = 9.3 Hz, 1H), 4.49-4.39 (m, 4H), 4.36 (s, 1H), 4.22 (dd, J =16.0, 5.3 Hz, 1H), 3.79 (s, 1H), 3.69-3.66 (m, 2H), 3.46-3.42 (m, 1H),3.05-3.01 (m, 2H), 2.83 (d, J = 16.8 Hz, 1H), 2.68 (p, J = 1.9 Hz, 2H),2.44 (s, 3H), 2.33 (p, J = 1.9 Hz, 3H), 2.09-2.01 (m, 4H), 1.91 (s, 4H),1.58-1.55 (m, 1H), 1.15 (s, 1H), 1.08 (d, J = 6.2 Hz, 4H), 0.93 (s, 9H)J88

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [(1R,2S,5S)-3- azabicyclo[3.1.0]hexan-2-ylformamido]- 5-carbamoylpentan- 2- yl]oxy]methyl)phenyl]pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide858.35 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.59 (t, J = 6.1 Hz,1H), 7.92-7.83 (m, 2H), 7.72 (d, J = 9.3 Hz, 1H), 7.46-7.32 (m, 5H),7.29 -7.18 (m, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.70 (s, 1H), 4.55 (d, J =9.4 Hz, 1H), 4.51-4.38 (m, 4H), 4.36 (s, 1H), 4.22 (dd, J = 15.9, 5.3Hz, 1H), 3.77 (d, J = 8.1 Hz, 1H), 3.66 (t, J = 8.8 Hz, 2H), 3.60-3.52(m, 1H), 3.52-3.40 (m, 1H), 3.00-2.89 (m, 1H), 2.86-2.76 (m, 1H), 2.71(q, J = 7.1 Hz, 4H), 2.56 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 2.37-2.26(m, 1H), 2.15 (dt, J = 13.9, 6.7 Hz, 1H), 2.03 (tdd, J = 14.7, 9.4, 4.0Hz, 2H), 1.91 (ddd, J = 13.1, 8.7,4.6 Hz, 1H), 1.63-1.43 (m, 4H), 1.35(td, J = 7.3, 3.8 Hz, 1H), 1.15-1.06 (m, 4H), 0.94 (s, 9H), 0.33 (q, J =4.2 Hz, 1H), 0.25 (td, J = 7.7, 4.6 Hz, 1H) J89

(2S,4R)-1-[(2S)-2- [5-(4-[[(2S)-2- [[(2S,11S)-11- Amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]methyl]phenyl)pentan amido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide 977.35 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.39 (d, J= 7.9 Hz, 1H), 7.84 (td, J = 15.3, 14.3, 8.6 Hz, 2H), 7.45-7.35 (m, 4H),7.24-7.12 (m, 4H), 7.11-6.89 (m, 4H), 6.71 (s, 1H), 5.11 (d, J = 8.3 Hz,1H), 5.01 (dt, J = 11.0, 3.4 Hz, 1H), 4.92 (p, J = 6.9 Hz, 1H), 4.52 (d,J = 9.3 Hz, 1H), 4.42 (t, J = 3.9 Hz, 3H), 4.31- 4.25 (m, 1H), 3.86-3.77(m, 1H), 3.6 (dd, J = 15.8, 11.7 Hz, 2H), 3.53-3.42 (m, 1H), 3.14-2.64(m, 5H), 2.56 (d, J = 10.0 Hz, 3H), 2.46 (s, 3H), 2.37-2.21 (m, 1H),2.21-1.85 (m, 5H), 1.79 (ddt, J = 13.2, 9.5, 4.5 Hz, 2H), 1.68-1.42 (m,6H), 1.38 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 3.0 Hz, 1H), 1.14-1.03 (m,1H), 0.9 4 (s, 9H) J146

(2S,4R)-1-[(2S)-2- (6-[3-[(3R)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentyl] phenyl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide 961.40 ¹H NMR (400 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 7.84 (dd, J = 10.9,9.1 Hz, 2H), 7.41 (q, J = 8.4 Hz, 4H), 7.21-7.10 (m, 2H), 7.07 (d, J =7.1 Hz, 1H), 7.05-6.88 (m, 5H), 6.69 (s, 1H), 5.14 (s, 1H), 5.07-4.97(m, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.49-4.39 (m, 2H), 4.36 (s, 1H), 4.22(dd, J = 15.9, 5.4 Hz, 1H), 3.72-3.61 (m, 3H), 3.51- 3.39 (m, 3H), 3.02(d, J = 6.3 Hz, 2H), 2.91 (dd, J = 16.7, 3.5 Hz, 1H), 2.61-2.54 (m, 1H),2.45 (s, 3H), 2.32-2.19 (m, 1H), 2.18-2.08 (m, 3H), 2.05 (d, J = 8.1 Hz,3H), 2.00-1.86 (m, 3H), 1.75-1.59 (m, 4H), 1.58-1.41 (m, 5H), 1.27 (q, J= 7.6 Hz, 2H), 0.94 (s, 9H)

(2S)-2-1[[(5S,8S,10aR)-5-amino-3-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hexanoyl]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-N-(diphenylmethyl)pentanediamide;trifluoroacetic acid (Intermediate J73)

The titled compound was prepared according to Step 4 to prepareIntermediate G. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.86 (t,J=8.4 Hz, 1H), 8.40-8.25 (m, 4H), 7.38-7.21 (m, 11H), 7.07-6.97 (m, 2H),6.87 (dt, J=8.1, 1.8 Hz, 1H), 6.79 (s, 1H), 6.10 (d, J=8.4 Hz, 1H), 5.34(dd, J=12.8, 5.4 Hz, 1H), 4.56-4.31 (m, 4H), 4.19 (dd, J=11.3, 5.7 Hz,1H), 3.95 (d, J=14.3 Hz, 1H), 3.81 (s, 1H), 3.50-3.35 (m, 1H), 3.33 (s,3H), 3.25-3.08 (m, 1H), 3.05-2.81 (m, 2H), 2.77-2.56 (m, 5H), 2.46-2.26(m, 1H), 2.25-1.44 (m, 12H), 1.45-1.18 (m, 2H); MS (ESI, m/z):[(M−1)]⁻=874.10.

The following intermediates in Table 53 were prepared according to theprocedure of Step 4 of the procedure to prepare Intermediate G.

TABLE 53 Characterization data for intermediates prepared according toabove. MS: Intermediate Structure Chemical Name [(M +1 )]⁺ ¹H NMR J74

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[7-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]heptanoyl]-6-oxo-octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formanido]-N-(diphenylmethyl)- pentanediamide; trifluoroacetic acid  890.6 (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.85 (t, J = 8.0 Hz, 1H), 8.39- 8.21 (m, 3H),7.39-7.18 (m, 11H), 7.07-6.94 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 6.81(s, 1H), 6.11 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 12.8, 5.4 Hz, 1H),4.53-4.30 (m, 4H), 4.18 (d, J = 15.3 Hz, 1H), 3.96 (d, J = 14.1 Hz, 1H),3.81 (d, J = 14.0 Hz, 1H), 3.56-3.33 (m, 1H), 3.27 (s, 3H), 3.28-3.08(m, 1H), 3.04-2.83 (m, 1H), 2.78-2.68 (m, 1H), 2.68- 2.57 (m, 4H),2.50-2.24 (m, 2H), 2.25-2.05 (m, 3H), 2.05-1.85 (m, 3H), 1.85-1.65 (m,4H), 1.65-1.43 (m, 4H), 1.34 (m, 4H). J75

(2S)2- [[5S,8S,10aR)-5- amino-3-[8-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]octanoyl]-6-oxo-octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-N-(diphenylmethyl)- pentanediamide; trifluoroacetic acid  904.6 (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.85 (t, J = 8.9 Hz, 1H), 8.31 (m, 3H),7.40-7.29 (m, 4H), 7.26 (m, 7H), 7.05-6.97 (m, 2H), 6.86 (d, J = 8.1 Hz,1H), 6.79 (s, 1H), 6.10 (d, J = 8.3 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz,1H), 4.54-4.25 (m, 4H), 4.25-4.20 (m, 2H), 4.03- 3.71 (m, 1H), 3.52-3.36(m, 1H), 3.34 (s, 3H), 3.27-3.05 (m, 1H), 3.05-2.83 (m, 1H), 2.83-2.57(m, 4H), 2.46-1.64 (m, 13H), 1.60- 1.45 (m, 4H), 1.35-1.25 (m, 6H). J76

(2S)-2- [[5S,8S,10aR)-5- amino-3-[5-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 1,3-benzodiazol-4- yl]pentanoyl]-6-oxo-octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-N-(diphenylmethyl)- pentanediamide; trifluoroacetic acid  862.4 (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.84 (t, J = 9.4 Hz, 1H), 8.36- 5.24 (m, 4H),7.39-7.17 (m, 11H), 7.04-6.93 (m, 2H), 6.88 (s, 1H), 6.78 (s, 1H), 6.10(d, J = 8.1 Hz, 1H), 5.37 (dd, J = 12.6, 5.5 Hz, 1H), 4.51-4.33 (m, 4H),4.26-4.12 (m, 1H), 3.96 (d, J = 14.1 Hz, 1H), 3.83 (d, J = 14.3 Hz, 1H),3.58 (s, 3H), 3.51-3.38 (m, 1H), 3.27-3.06 (m, 1H), 3.03-2.82 (m, 5H),2.79- 2.51 (m, 3H), 2.50-2.31 (m, 2H), 2.25-2.05 (m, 2H), 1.96-1.59 (m,9H). J77

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[8-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 1,3-benzodiazol-4- yl]octanoyl]-6-oxo-octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-N-(diphenylmethyl)- pentanediamide; trifluoroacetic acid  904.6 (400 MHz,DMSO-d₆) δ 11.11 (s, 1H), 8.86 (t, J = 8.4 Hz, 1H), 8.37- 8.23 (m, 4H),7.40-7.19 (m, 11H), 7.04-6.93 (m, 2H), 6.86 (dd, J = 5.7, 3.3 Hz, 1H),6.79 (s, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.37 (dd, J = 12.5, 5.4 Hz, 1H),4.56-4.33 (m, 4H), 4.28-4.10 (m, 1H), 4.07-3.91 (m, 1H), 3.81 (d, J =11.7 Hz, 1H), 3.64-3.58 (m, 1H), 3.55 (s, 3H), 3.47 (d, J = 15.4 Hz,1H), 3.27- 3.08 (m, 1H), 3.05-2.82 (m, 4H), 2.78-2.57 (m, 2H), 2.50-2.30(m, 2H), 2.24-2.05 (m, 2H), 2.05-1.47 (m, 8H), 1.45-1.27 (m, 6H). J78

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[8-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H- isoindol-4-yl]oct-7- ynoyl]-6-oxo- octahydropyrrolo[1,2-a][1,5]diazocin-8- yl]formamido]-N- (diphenylmethyl)- pentanediamide;trifluoroacetic acid  885.6 (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.85 (t,J = 8.7 Hz, 1H), 8.30 (m, 4H), 7.72 (dd, J = 7.5, 1.2 Hz, 1H), 7.63 (dd,J = 7.6, 1.1 Hz, 1H), 7.53 (td, J = 7.6, 1.5 Hz, 1H), 7.37- 7.20 (m,12H), 6.79 (s, 1H), 6.10 (d, J = 8.3 Hz, 1H), 5.16 (dd, J = 13.3, 5.1Hz, 1H), 4.52-4.28 (m, 5H), 4.19 (dq, J = 16.2, 5.5, 4.8 Hz, 2H), 3.96(d, J = 14.3 Hz, 1H), 3.82 (t, J = 14.0 Hz, 1H), 3.46 (d, J = 11.3 Hz,1H), 3.27-3.06 (m, 1H), 3.06-2.83 (m, 2H), 2.66-2.55 (m, 2H), 2.50-2.27(m, 2H), 2.27- 1.39 (m, 16H). J90

1-[4-([[(2R,3S)-3- [[2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]-N-[(2S)-1- [(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]piperidine-4- carboxamide hydrochloride 1041.72 Used inthe next step without further purification J91

(2S,4R)-1-[(2S)-2- (2-[1-[4-([[(2R,3S)- 3-[[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]piperidin-4- yl]acetamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide hydrochloride 1018.51 (400 MHz, DMSO-d₆) δ9.02 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.48 (d, J = 16.6 Hz, 3H), 8.07(d, J = 8.9 Hz, 1H), 7.79 (s, 1H), 7.45- 7.38 (m, 6H), 7.23 (s, 1H),7.10 (t, J = 8.2 Hz, 2H), 7.06-7.01 (m, 1H), 6.75 (s, 1H), 5.14 (dd, J =10.9, 3.0 Hz, 1H), 4.58 (d, J = 9.3 Hz, 1H), 4.50-4.41 (m, 5H), 4.35 (d,J = 9.8 Hz, 2H), 4.25-4.19 (m, 5H) 3.84 (d, J = 4.6 Hz, 1H), 3.54- 3.41(m, 6H), 3.15 (t, J = 7.9 Hz, 2H), 2.86 (d, J = 16.2 Hz, 1H), 2.46 (s,3H), 2.23 (d, J = 13.8 Hz, 2H), 2.23-2.03 (m, 6H), 1.97-1.71 (m, 6H),1.61 (s, 1H), 1.11 (d, J = 6.3 Hz, 3H), 0.97 (s, 9H) J92

(2S,4R)-1-[(2S)-2- (3-1l-[4-([[2R,3S)- 3-[[(2S,11S)-11- amino-12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido)-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]piperidin-4- yl]propanamido)- 3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide hydrochloride 1032.80 (400 MHz, DMSO-d₆) δ9.02 (s, 1H), 8.60 (t, J = 6.1 Hz, 1H), 8.53- 8.47 (m, 3H), 8.07 (d, J =9.3 Hz, 1H), 7.98 (d, J = 9.3 Hz, 1H), 7.78 (s, 2H), 7.41 (q, J = 8.4Hz, 7H), 7.16-6.96 (m, 3H), 6.75 (s, 1H), 5.14 (dd, J = 10.9, 3.1 Hz,1H), 4.57 (d, J = 9.3 Hz, 1H), 4.53-4.40 (m, 3H), 4.39-4.31 (m, 1H),4.30- 4.17 (m, 6H), 3.90-3.77 (m, 2H), 3.72-3.66 (m, 2H), 3.54-3.42 (m,2H), 3.17-3.13 (m, 1H), 2.86 (d, J = 16.7 Hz, 1H), 2.45 (s, 3H), 2.41-2.18 (m, 4H), 2.20-1.97 (m, 4H), 1.97-1.71 (m, 5H), 1.71-1.44 (m, 5H),1.11 (d, J = 6.2 Hz, 3H), 0.96 (s, 9H) J93

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(1R,2S,5S)-3- [(2S)-2-amino-4-methylpentanoyl]-3- azabicyclo[3.1.0] hexan-2- yl]formamido]-5-carbamoylpentan- 2- yl]oxy]methyl)- phenyl]pentanamido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxainide hydrochloride  971.35 (400MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.22- 8.18 (m,2H), 7.87-7.83 (m, 2H), 7.41 (q, J = 8.3Hz, 4H), 7.23 (d, J = 7.9 Hz,2H), 7.14 (d, J = 7.7 Hz, 2H), 7.05 (s, 1H), 6.72 (s, 1H), 4.54 (d, J =9.3 Hz, 1H), 4.50-4.39 (m, 4H), 4.34-4.30 (m, 4H), 3.94- 3.92 (m, 2H),3.79-3.61 (m, 2H), 3.47 (d, J = 9.9 Hz, 2H), 3.43-3.35 (m, 2H), 2.56 (t,J = 7.5 Hz, 1H), 2.45 (s, 3H), 2.39-2.25 (m, 1H), 2.12-2.05 (m, 3H),1.96-1.73 (m, 2H), 1.55-1.50 (m, 7H), 1.18-1.05 (m, 4H), 0.93-0.87 (m,16H), 0.68- 0.65 (m, 1H), 0.63-0.56 (m, 1H). J94

(2S)-2-[[2S,11S)- 11-amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )} [4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-N-[[4-(3-[[(2S)-1- [(2S,4R)-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) phenyl]methyl] pentanediamidehydrochloride  962.40 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J =6.1 Hz, 1H), 8.33 (t, J = 5.9 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.92(d, J = 9.3 Hz, 1H), 7.43-7.38 (m, 4H), 7.27 (s, 1H), 7.15-7.07 (m, 4H),7.06-7.02 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.76 (s, 1H), 5.15-5.06 (m,2H), 4.56 (d, J = 9.4 Hz, 1H), 4.47-4.39 (m, 2H), 4.35 (s, 1H),4.26-4.17 (m, 4H), 4.11 (q, J = 5.3 Hz, 1H), 3.67 (d, J = 3.6 Hz, 2H),3.46 (dd, J = 9.5, 2.6 Hz, 1H), 3.33-3.29 (m, 2H), 3.17 (d, J = 5.0 Hz,2H), 3.04 (d, J = 12.5 Hz, 2H), 2.97-2.92 (m, 1H), 2.45 (s, 3H),2.35-2.26 (m, 1H), 2.20-2.13 (m, 1H), 2.15-2.08 (m, 2H), 2.05-1.96 (m,2H), 1.94- 1.86 (m, 3H), 1.82-1.72 (m, 3H), 0.95 (s, 9H) J95

(2,S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )} [4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[[4-(4-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl)butyl) phenyl]methyl] pentanediamidehydrochloride  976.50 (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.59 (t, J =6.1 Hz, 1H), 8.45 (d, J = 14.8 Hz, 3H), 8.44-8.36 (m, 1H), 7.89 (d, J =9.3 Hz, 1H), 7.41 (q, J = 8.4 Hz, 4H), 7.31 (s, 1H), 7.13-7.05 (m, 6H),7.01 (t, J = 7.4 Hz, 1H), 6.80 (s, 1H), 5.17 (dd, J = 11.0, 3.0 Hz, 1H),4.58-4.51 (m, 1H), 4.46-4.43 (m, 2H), 4.35 (s, 1H), 4.25-4.17 (m, 6H),3.53-3.41 (m, 1H), 3.41-3.39 (m, 1H), 3.14 (d, J = 6.8 H,. 2H),3.00-2.87 (m, 1H), 2.56-2.53 (m, 2H), 2.45 (s, 3H), 2.35-2.03 (m, 7H),1.90-1.80 (m, 2H), 1.80-1 75 (m, 1H), 1.53- 1.48 (m, 4H), 0.93 (s, 9H)J96

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[[4-(5-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenyl]methyl] pentanediamidehydrochloride  990.40 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.58 (m, J =6.1 Hz, 1H), 8.51-8.38 (m, 4H), 7.86 (d, J = 9.3 Hz, 1H), 7.41 (m, J =8.3 Hz, 4H), 7.31 (s, 1H), 7.13-7.06 (m, 6H), 7.01-6.99 (m, 1H), 6.80(s, 1H), 5.17 (dd, J = 10.9, 3.0 Hz, 1H), 4.57-4.51 (m, 1H), 4.47-4.40(m, 2H), 4.36-4.34 (m, 1H), 4.24- 4.198 (m, 4H), 3.71-3.61 (m, 2H),3.50-3.47 (m, 2H), 3.14 (d, J = 6.3 Hz, 2H), 2.96-2.94 (m, 1H), 2.45 (s,3H), 2.36-2.00 (m, 9H), 1.91- 1.89 (m, 2H), 1.84-1.75 (m, 1H), 1.53-1.48(m, 4H), 1.29-1.22 (m, 3H), 0.93 (s, 9H) J97

(2S,4R)-1-[(2S)-2- [2-[4-([[2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)-[1,1- biphenyl]-3- y]|acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide hydrochloride 1011.47 (400 MHz, DMSO-d₆) δ9.06 (s, 1H), 8.61 (t, J = 6.1 Hz, 1H), 8.51 (m, 3H), 8.19 (d, J = 9.4Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.59 (s, 1H), 7.55 (d, J = 8.0 Hz,2H), 7.50 (d, J = 7.8 Hz, 1H), 7.46-7.37 (m, 6H), 7.35 (d, J = 8.1 Hz,2H), 7.28 (d, J = 7.7 Hz, 1H), 7.07 (t, J = 6.3 Hz, 2H), 7.00 (t, J =7.4 Hz, 1H), 6.76 (s, 1H), 5.15 (dd, J = 10.9, 3.1 Hz, 1H), 4.56 (d, J =9.3 Hz, 2H), 4.50-4.46 (m, 4H), 4.43 (d, J = 7.0 Hz, 1H), 4.35 (s, 1H),4.25 (d, J = 5.2 Hz, 1H), 4.21 (d, J = 5.4 Hz, 1H), 3.89-3.83 (m, 1H),3.77 (d, J = 13.9 Hz, 1H), 3.68-3.63 (m, 2H), 3.14 (d, J = 6.1 Hz, 2H),2.88 (d, J = 16.7 Hz, 1H), 2.46 (s, 3H), 2.24 (d, J = 13.1 Hz, 1H),2.15-2.13 (m, 1H), 2.07-2.03 (m, 4H), 1.92-1.89 (m, 1H), 1.82-1.79 (m,1H), 1.64- 1.62 (m, 1H), 1.13 (d, J = 6.3 Hz, 3H), 0.94 (s, 9H) J98

(2S,4R)-1-[(2S)-3,3- dimethyl-2-[[(1r,3r)- 3-[[4-([[2R,3S)-3-[[(2S,11S)-11- amino-12-oxo-1- azatricyclo [6.4.1.0{circumflex over ( )}[4,13])trideca- 4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl) phenyl]methyl] cyclobutyl] formamido]butanoyl]-4-hydroxy-N- [[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl]pyrrolidine-2- carboxamide hydrochloride 1089.54 (400 MHz, DMSO-d₆) δ9.01 (d, J = 1.9 Hz, 1H), 8.57 (s, 1H), 8.01 (d, J = 9.3 Hz, 1H), 7.69(d, J = 9.1 Hz, 1H), 7.46-7.35 (m, 4H), 7.19 (s, 1H), 7.14 (d, J = 7.8Hz, 3H), 7.10-7.00 (m, 6H), 6.74 (s, 1H), 5.14 (s, 1H), 5.06 (dd, J =10.8, 2.7 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.48-4.32 (m, 5H), 4.22(dd, J = 15.9, 5.5 Hz, 1H), 4.05 (t, J = 8.7 Hz, 1H), 3.79 (s, 1H), 3.67(s, 2H), 3.50-3.36 (m, 2H), 3.11-2.95 (m, 2H), 2.86 (d, J = 16.6 Hz,1H), 2.65 (dd, J = 33.6, 7.6 Hz, 2H), 2.45 (s, 3H), 2.43-2.32 (m, 1H),2.22-1.97 (m, 3H), 1.96-1.84 (m, 2H), 1.78 (q, J = 9.5 Hz, 2H), 1.58-1.54 (m, 1H), 1.40-1.38 (m, 2H), 1.25-1.23 (m, 1H), 1.08 (d, J = 6.3 Hz,3H), 0.93 (s, 9H) J99

(2S,4R)-1-[(2S)-2- [2-(3-[[4-([[(2R,3S)- 3-[[(2S,11S)-11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflex over ( )}[4,13]]trideca- 4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2-yl]oxy]methyl)- phenyl]methyl]- cyclobutyl)acetamido]- 3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide hydrochloride 1003.35 (400MHz, CD₃OD) δ 9.96 (s, 1H), 7.62-7.51 (m, 4H), 7.25-7.18 (m, 2H), 7.13(d, J = 7.4 Hz, 1H), 7.08 (dt, J = 11.6, 7.4 Hz, 4H), 5.20 (dd, J =11.0, 3.5 Hz, 1H), 4.66-4.53 (m, 4H), 4.50 (s, 2H), 4.46-4.35 (m, 1H),4.25-4.16 (m, 1H), 4.07- 3.99 (m, 1H), 3.90 (d, J = 11.1 Hz, 1H),3.85-3.73 (m, 1H), 3.68 (s, 3H), 3.66-3.55 (m, 2H), 3.55-3.46 (m, 1H),3.27 (dd, J = 8.1, 4.7 Hz, 2H), 3.09-3.00 (m, 1H), 2.76 (d, J = 7.7 Hz,1H), 2.66 (d, J = 7.3 Hz, 1H), 2.62 (s, 3H), 2.54-2.16 (m, 6H),2.14-1.97 (m, 1H), 1.96-1.81 (m, 1H), 1.78-1.65 (m, 1H), 1.59- 1.41 (m,2H), 1.31 (s, 1H), 1.21 (s, 3H), 1.04 (s, 9H) J100

(2S,4R)-1-[(2S,)-2- (2-[3-[4-([[2R,3S)- 3-[[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)-phenyl]cyclobutyl] acetamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide hydrochloride  989.05 (400 MHz, CD₃OD) δ 9.99(dd, J = 5.1. 2.0 Hz, 1H), 7.63-7.51 (m, 4H), 7.29-7.02 (m, 7H), 5.20(ddd, J = 11.1, 3.6, 1.6 Hz, 1H), 4.67 (d, J = 4.7 Hz, 1H), 4.64-4.36(m, 6H), 4.25-4.16 (m, 1H), 4.07-3.99 (m, 1H), 3.93 (d, J = 11.0 Hz,1H), 3.89-3.67 (m, 2H), 3.63 (d, J = 12.5 Hz, 1H), 3.60-3.46 (m, 1H),3.42-3.33 (m, 1H), 3.30-3.23 (m, 3H), 3.08-2.97 (m, 1H), 2.74-2.62 (m,1H), 2.62 (s, 3H), 2.61-2.50 (m, 1H), 2.49-2.20 (m, 6H), 2.15- 1.97 (m,2H), 1.88-1.84 (m, 1H), 1.79-1.67 (m, 1H), 1.59-1.55 (m, 1H), 1.21 (s,3H), 1.06 (s, 9H) J101

(2S,4R)-1-[(2S)-2- [2-(4-[[4-([[2R,3S)- 3-[[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)-phenyl]- methyl]piperidin- 1-yl)acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide trifluoroacetate 1032.70 (400 MHz, DMSO-d₆) δ8.99 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 8.33 (s, 1H), 7.78 (d, J = 9.7Hz, 1H), 7.43 (s, 4H), 7.29-7.16 (m, 3H), 7.09 (d, J = 7.8 Hz, 2H),6.85-6.50 (m, 2H), 4.53-4.23 (m, 8H), 3.83- 3.52 (m, 5H), 3.50-3.38 (m,6H), 3.10-2.67 (m, 5H), 2.49-2.44 (m, 4H), 2.12-1.98 (m, 4H), 1.95-1.67(m, 3H), 1.66-1.42 (m, 5H), 1.42- 1.36 (m, 3H), 1.24-1.20 (m, 3H), 1.06(d, J = 6.0 Hz, 3H), 0.94 (s, 9H). J102

(2S,4R)-1-[(2S)-2- (6-[4-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] phenyl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide hydrochloride  963.35 (400MHz, DMSO-d6) δ 9.06 (s, 1H), 8.62-8.42 (m, 4H), 8.26 (d, J = 8.2 Hz,1H), 7.85 (d, J = 9.3 Hz, 1H), 7.41 (q, J = 8.4 Hz, 4H), 7.13- 6.94 (m,6H), 6.85-6.74 (m, 2H), 5.10 (dd, J = 10.9, 3.0 Hz, 1H), 4.56-4.48 (m,1H), 4.48-4.15 (m, 6H), 4.03-3.82 (m, 2H), 3.71-3.63 (m, 2H), 3.49-3.41(m, 1H), 3.14 (d, J = 6.8 Hz, 2H), 2.88-2.84 (m, 1H), 2.46 (s, 3H),2.32-1.98 (m, 6H), 1.98-1.66 (m, 4H), 1.58-1.42 (m, 6H), 1.32-1.24 (m,4H), 0.93 (s, 9H) J103

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] phenyl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide hydrochloride  963.42 (400MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.53- 8.47 (m,2H), 8.24 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.45- 7.36 (m,4H), 7.17 (dd, J = 8.8, 7.6 Hz, 1H), 7.08 (d, J = 7.7 Hz, 2H), 7.04-6.96(m, 1H), 6.78-6.72 (m, 4H), 5.10 (dd, J = 10.9, 3.0 Hz, 1H), 4.54 (d, J= 9.3 Hz, 1H), 4.48- 4.39 (m, 2H), 4.35 (s, 1H), 4.30- 4.24 (m, 4H),3.99-3.86 (m, 4H), 3.72-3.60 (m, 2H), 3.49-3.35 (m, 3H), 3.17-3.13 (m,2H), 2.86 (d, J = 16.8 Hz, 1H), 2.45 (s, 3H), 2.32- 1.99 (m, 4H),1.96-1.65 (m, 3H), 1.63-1.40 (m, 4H), 1.34-1.17 (m, 3H), 1.10 (t, J =7.0 Hz, 2H), 0.93 (s, 9H) J104

(2S,4R)-1-[(2S)-2- [3-(4-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] propyl]phenyl)propanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamidehydrochloride  963.21 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.57 (t, J =6.0 Hz, 1H), 8.37 (s, 2H), 8.11-8.03 (m, 1H), 7.92 (d, J = 9.5 Hz, 1H),7.41 (q, J = 8.3 Hz, 4H), 7.21 (s, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.07(d, J = 7.8 Hz, 2H), 7.01-6.96 (m, 1H), 6.75 (s, 1H), 5.13-5.03 (m, 1H),4.55 (d, J = 8.7 Hz, 1H), 4.48-4.38 (m, 2H), 4.36 (s, 1H), 4.25-4.20 (m,3H), 3.80 (s, 1H), 3.66 (s, 2H), 3.62- 3.54 (m, 5H), 3.41-3.30 (m, 2H),3.15 (s, 2H), 2.93-2.74 (m, 3H), 2.57 (s, 2H), 2.45 (s, 3H), 2.18 (d, J= 12.5 Hz, 1H), 2.09 (d, J = 9.0 Hz, 4H), 1.96-1.86 (m, 1H), 1.79- 1.69(m, 2H), 1.50 (d, J = 85.9 Hz, 2H), 1.28-1.22 (m, 1H), 1.16-1.06 (m,1H), 0.89 (s, 9H) J105

(2S,4R)-1-[(2S)-2- [5-(4-([[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- (methyl)amino]methyl)phenyl] pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamidehydrochloride  976.65 (400 MHz, DMSO-d₆) δ 10.37 (d, J = 138.2 Hz, 1H),9.01 (s, 1H), 8.64-8.40 (m, 5H), 7.88 (d, J = 9.3 Hz, 1H), 7.52 (dd, J =12.7, 7.8 Hz, 2H), 7.41 (q, J = 8.2 Hz, 5H), 7.32- 7.22 (m, 3H),7.17-6.98 (m, 4H), 6.80 (s, 1H), 5.13-5.04 (m, 1H), 4.59-4.52 (m, 1H),4.47-4.41 (m, 2H), 4.38-4.33 (m, 2H), 4.26-4.12 (m, 3H), 3.70-3.59 (m,2H), 3.54- 3.37 (m, 1H), 3.20-3.11 (m, 5H), 2.72-2.56 (m, 3H), 2.45 (s,3H), 2.38-1.99 (m, 6H), 1.95-1.88 (m, 1H), 1.82-1.74 (m, 1H), 1.67-1.48(m, 6H), 0.94 (s, 9H) J106

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]pentanamido]- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  991.70 (400 MHz, CD₃OD) δ 9.99 (s, 1H),7.61-7.46 (m, 4H), 7.23 (d, J = 8.1 Hz, 2H), 7.17-7.02 (m, 5H), 5.20(dd, J = 11.0, 3.6 Hz, 1H), 5.04 (q, J = 6.9 Hz, 1H), 4.58-4.50 (m, 3H),4.50-4.46 (m, 1H), 4.38 (q, J = 4.6 Hz, 1H), 4.25-4.16 (m, 1H), 4.03(dd, J = 10.5, 5.1 Hz, 2H), 3.64-3.47 (m, 2H), 3.27 (dd, J = 8.3, 4.7Hz, 2H), 3.04 (dd, J = 16.8, 3.6 Hz, 1H), 2.63 (s, 3H), 2.47-2.21 (m,5H), 2.05-1.95 (m, 1H), 1.90-1.86 (m, 1H), 1.70-1.64 (m, 9H), 1.62 (s,1H), 1.53 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.06 (s, 9H)J107

(2S,4R)-1-[(2S)-2- [10-[(2S)-2- [[2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),57-trien-2- yl]formamido]-4- carbamoylbutoxy] decanamido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide hydrochloride  943.15 (400MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.64-8.42 (m, 4H), 8.05 (d, J = 8.5 Hz,1H), 7.85 (d, J = 9.3 Hz, 1H), 7.47-7.35 (m, 5H), 7.09-7.06 (m, 2H),7.04-6.94 (m, 1H), 5.08 (dd, J = 10.9, 3.0 Hz, 1H), 4.46- 4.31 (m, 3H),4.29-4.11 (m, 1H), 3.72-3.61 (m, 2H), 3.49-3.41 (m, 1H), 3.37-3.24 (m,4H), 3.17-3.12 (m, 2H), 2.87 (dd, J = 17.0, 3.0 Hz, 1H), 2.46 (s, 3H),2.31-2.23 (m, 2H), 2.17-1.97 (m, 5H), 1.94- 1.87 (m, 1H), 1.77-1.67 (m,1H), 1.55-1.39 (m, 1H), 1.28-1.20 (m, 18H), 0.94 (s, 9H) J108

(2S,4R)-1-[(2S)-2- [9-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido-4- carbamoylbutoxy] nonanamido]-3,3-dimethylbutanoy]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide hydrochloride  929.40 (400MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.65-8.41 (m, 3H), 8.05 (d, J = 8.5 Hz,1H), 7.85 (d, J = 9.2 Hz, 1H), 7.41 (q, J = 8.1 Hz, 4H), 7.04 (dt, J =33.6, 7.4 Hz, 3H), 5.08 (dd, J = 11.1, 2.9 Hz, 1H), 4.55 (d, J = 9.1 Hz,1H), 4.46-4.38 (m, 2H), 4.36-4.34 (m, 1H), 4.28-4.11 (m, 2H), 3.78-3.76(m, 1H), 3.71-3.60 (m, 2H), 3.52-3.24 (m, 6H), 3.15- 3.13 (m, 2H), 2.88(d, J = 16.8 Hz, 1H), 2.46 (s, 3H), 2.28-2.24 (m, 2H), 2.13-2.08 (m,4H), 1.91 (d, J = 6.4 Hz, 1H), 1.76-1.75 (m, 1H), 1.52-1.40 (m, 6H),1.26-1.20 (m, 10H), 0.94 (s, 9H). J109

(3S,6S)-3-amino-N- ((S)-5-amino-1-((8- (((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)- 3,3-dimethyl-1- oxobutan-2- yl)amino)-8-oxooctyl)oxy)-5- oxopcntan-2-yl)-4- oxo-1,2,3,4,6,7- hexahydroazepino[3,2,1-hi]indole-6- carboxamide hydrochloride  915.50 (400 MHz, DMSO-d₆) δ9.01 (s, 1H), 8.62-8.33 (m, 3H), 8.03 (d, J = 8.4 Hz, 1H), 7.85 (d, J =9.3 Hz, 1H), 7.41 (q, J = 8.3 Hz, 4H), 7.23 (s, 1H), 7.13-6.97 (m, 3H),6.75(s, 1H), 5.08 (dd, J = 10.9, 3.0 Hz, 1H), 4.59-4.15 (m, 6H),3.52-3.25 (m, 4H), 3.18-3.11 (m, 3H), 2.92- 2.84 (m, 1H), 2.73-2.63 (m,1H), 2.45 (s, 3H), 2.35-2.15 (m, 3H), 2.15-1.85 (m, 4H), 1.78-1.65 (m,1H), 1.60-1.42 (m, 5H), 1.31-1.18 (m, 8H), 0.94 (s, 9H), 0.93-0.90 (m,1H) J110

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[[3-(4-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamoyl]butyl) phenyl]methyl]- pentanediamidehydrochloride  976.43 (300 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.60-8.35 (m,7H), 7.86 (d, J = 9.3 Hz, 1H), 7.46-7.35 (m, 5H), 7.30 (s, 1H), 7.17 (t,J = 7.7 Hz, 1H), 7.10-6.99 (m, 8H), 6.78 (s, 1H), 5.17 (dd, J = 10.9,3.0 Hz, 2H), 4.60-4.49 (m, 1H), 4.49-4.31 (m, 2H), 4.26-4.16 (m, 4H),3.73- 3.59 (m, 4H), 3.47-3.38 (m, 1H), 3.16-3.11 (m, 2H), 2.99-2.92 (m,1H), 2.44 (s, 3H), 2.32-1.97 (m, 6H), 1.97-1.71 (m, 2H), 1.49 (d, J =3.7 Hz, 4H), 0.93 (s, 9H) J111

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)-2-fluorophenyl] pentanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-(4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1109.45 (400 MHz, DMSO-d₆) δ 9.01 (s, 1H),8.41 (s, 3H), 8.04 (d, J = 9.4 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.44(d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.22-7.14 (m, 2H), 7.03(dd, J = 20.5, 7.2 Hz, 5H), 6.75 (s, 1H), 5.13 (d, J = 11.2 Hz, 1H),4.92 (t, J = 7.1 Hz, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.43 (s, 3H), 4.28(s, 1H), 4.24-4.16 (m, 2H), 3.51-3.39 (m, 2H), 3.15 (s, 2H), 2.85 (d, J= 16.6 Hz, 1H), 2.59 (s, 2H), 2.46 (s, 3H), 2.38-2.26 (m, 1H), 2.19-2.08(m, 4H), 2.07-2.03 (m, 1H), 2.04-2.00 (m, 2H), 1.86- 1.71 (m, 1H),1.62-1.58 (m, 1H), 1.58-1.43 (m, 6H), 1.40- 1.36 (m, 3H), 1.26-1.22 (m,1H), 1.10 (d, J = 6.3 Hz, 3H), 0.93 (s, 9H) J112

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] phenyl]hexanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  977.55 (400 MHz, CD₃OD) δ 10.02 (s, 1H), 7.56(q, J = 8.2 Hz, 4H), 7.22- 7.12 (m, 2H), 7.11-7.01 (m, 2H), 6.78 (m,3H), 5.25-5.13 (m, 1H), 5.03 (q, J = 7.0 Hz, 1H), 4.65-4.55 (m, 2H),4.44 (s, 1H), 4.30-4.16 (m, 3H), 4.08-3.96 (m, 2H), 3.89 (d, J = 10.9Hz, 1H), 3.72-3.63 (m, 1H), 3.62 (d, J = 1.5 Hz, 1H), 3.53- 3.47 (m,1H), 3.27 (t, J = 6.6 Hz, 3H), 3.03 (d, J = 16.5 Hz, 1H), 2.63-2.56 (m,3H), 2.49-2.15 (m, 4H), 2.05-2.01 (m, 1H), 1.97-1.89 (m, 1H), 1.62-1.57(m, 5H), 1.53 (d, J = 7.0 Hz, 3H), 1.44-1.27 (m, 4H), 1.04 (s, 9H) J113

(2S,4R)-1-[(2S)-2- [([3-[4-([[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl]propyl] carbamoyl) amino]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide trifluoroacetate  978.70 (400 MHz, DMSO-d₆) δ9.00 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.36 (s, 2H), 7.98 (s, 1H),7.44- 7.37 (m, 4H), 7.16 (d, J = 5.2 Hz, 4H), 7.12-7.07 (m, 5H), 6.14(d, J = 9.7 Hz, 1H), 5.12 (dd, J = 11.0, 3.1 Hz, 2H), 4.41 (s, 4H), 4.36(s, 1H), 4.27-4.19 (m, 1H), 3.86-3.82 (m, 1H), 3.48-3.44 (m, 3H), 3.15(s, 2H), 3.00 (d, J = 8.9 Hz, 3H), 2.87 (dd, J = 17.4, 3.0 Hz, 1H), 2.55(t, J = 7.5 Hz, 4H), 2.45 (s, 3H), 2.16- 2.00 (m, 7H), 1.96-1.87 (m,1H), 1.80-1.76 (m, 1H), 1.67-1.63 (m, 2H), 1.08 (s, 3H), 0.92 (s, 9H)J114

(2S,4R)-1-[(2S)-2- [9-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] non-7-ynamido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide hydrochloride  925.55 (400MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.54- 8.50 (m,2H), 8.18-8.06 (m, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.48-7.37 (m, 4H),7.11-7.04 (m, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.72 (s, 1H), 5.08 (dd, J =10.9, 3.1 Hz, 1H), 4.57-4.48 (m, 1H), 4.46-4.42 (m, 1H), 4.36-4.33 (m,1H), 4.30-4.13 (m, 1H), 4.12-4.08 (m, 2H), 3.85- 3.72 (m, 1H), 3.71-3.60(m, 2H), 3.52-3.39 (m, 1H), 3.39-3.25 (m, 2H), 3.15-3.11 (m, 2H), 2.88(dd, J = 17.0, 3.0 Hz, 1H), 2.46 (s, 3H), 2.36-2.01 (m, 13H), 1.92-1.87(m, 1H), 1.76-1.72 (m, 1H), 1.67-1.56 (m, 1H), 1.47-1.43 (m, 4H), 1.38-1.30-1.26 (m, 2H), 0.94 (s, 9H) J115

(2S,4R)-1-[(2S)-2- [(7Z)-9-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] non-7-enamido]-3,3-dimethylbutanoyl]- 4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5-yl)phenyl]methyl] pyrrolidine-2- carboxamide hydrochloride  927.40 (400MHz, DMSO-d₆) δ 9.11-9.03 (m, 1H), 8.58 (t, J = 6.0 Hz, 1H), 8.49 (s,2H), 7.85 (dd, J = 9.3, 2.1 Hz, 1H), 7.40 (t, J = 7.4 Hz, 4H), 7.27 (s,1H), 7.15-7.04 (m, 2H), 7.04-7.00 (m, 1H), 6.75 (s, 1H), 5.55-5.47 (m,1H), 5.11-5.04 (m, 1H), 4.57-4.53 (m, 1H), 4.47-4.39 (m, 2H), 4.35 (s,1H), 4.27-4.14 (m, 3H), 3.97 (d, J = 6.0 Hz, 1H), 3.76 (dd, J = 13.5,5.0 Hz, 1H), 3.71-3.61 (m, 2H), 3.57 (s, 5H), 3.46-3.40 (m, 1H), 3.39(q, J = 7.0 Hz, 1H), 3.36-3.28 (m, 1H), 3.13 (d, J = 6.3 Hz, 2H),2.98-2.81 (m, 1H), 2.46 (s, 3H), 2.30-2.20 (m, 2H), 2.14-1.99 (m, 6H),1.93-1.91 (m, 1H), 1.78-1.68 (m, 1H), 1.60 (s, 2H), 1.51-1.46 (m, 2H),1.39- 1.19 (m, 4H), 1.15-1.10 (m, 1H), 0.94 (s, 9H) J116

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] phenyl]butanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride 949.70 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.47 (s, 2H), 8.39 (d, J =7.8 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 15.6 Hz, 2H),7.19 (t, J = 7.7 Hz, 1H), 7.10 (dd, J = 13.8, 6.9 Hz, 2H), 7.05-6.97 (m,1H), 6.80-6.71 (m, 3H), 5.10 (dd, J = 10.9, 3.1 Hz, 1H), 4.96- 4.88 (m,1H), 4.54 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.35- 4.14 (m,4H), 3.97 (d, J = 13.8 Hz, 1H), 3.91 (s, 1H), 3.78-3.61 (m, 1H),3.53-3.37 (m, 1H), 3.18-3.14 (m, 3H), 2.89-2.85 (m, 1H), 2.47 (s, 3H),2.33-2.04 (m, 5H), 2.02- 1.98 (m, 1H), 1.87-1.77 (m, 2H), 1.78-1.71 (m,5H), 1.61-1.44 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H), 0.95 (s, 9H) J117

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- fluorophenyl]hexamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride[(M + 18)]⁺ = 995.23 (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.46 (s, 1H),8.44-8.35 (m, 2H), 8.27 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.48-7.35 (m, 3H), 7.27 (s, 1H), 7.10-6.97 (m, 6H), 6.87-6.77 (m, 2H),5.11-5.07 (m, 1H), 4.92 (t, J = 7.1 Hz, 1H), 4.55-4.48 (m, 2H),4.47-4.38 (m, 2H), 4.28 (s, 1H), 4.20 (d, J = 8.9 Hz, 2H), 3.73-3.59 (m,1H), 3.53- 3.37 (m, 1H), 3.14 (d, J = 5.1 Hz, 2H), 2.92-2.84 (m, 2H),2.59-2.55 (m, 2H), 2.46 (s, 3H), 2.32-2.17 (m, 2H), 2.17-2.13 (m, 3H),2.16- 2.06 (m, 1H), 2.06-1.97 (m, 1H), 1.85-1.74 (m, 1H), 1.78-1.70 (m,1H), 1.56-1.52 (m, 4H), 1.55-1.47 (m, 1H), 1.40-1.36 (m, 3H), 1.28 (s,3H), 0.93 (s, 9H) J118

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1S,4S)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]methyl]cyclohexyl]acetyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8-yl]formamido]-N- [(4- methane- sulfonylphenyl) methyl] pentanediamidetrifluoroacetate  918.50 (300 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.65-8.45(m, 1H), 8.45-8.14 (m, 3H), 7.91-7.75 (m, 2H), 7.50 (dd, J = 8.3, 4.0Hz, 2H), 7.22 (s, 1H), 7.08-6.92 (m, 2H), 6.92-6.71 (m, 2H), 5.33 (dd, J= 12.7, 5.4 Hz, 1H), 4.54-4.34 (m, 4H), 4.34-4.07 (m, 3H), 4.07-3.73 (m,2H), 3.58- 3.38 (m, 2H), 3.31 (s, 3H), 3.18 (s, 3H), 3.05-2.81 (m, 4H),2.79-2.55 (m, 5H), 2.38-2.08 (m, 4H), 2.08- 1.66 (m, 6H), 1.53-1.26 (m,8H) J119

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1S,4S)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]methyl]cyclohexyl]acetyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8-yl]formamido]-N- [(4- isosulfonylphenyl) methyl] pentanediamidetrifluoroacetate  882.45 (300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.53-8.12(m, 4H), 7.19 (d, J = 3.0 Hz, 5H), 7.09-6.96 (m, 2H), 6.84 (dd, J =13.1, 6.0 Hz, 3H), 5.36 (dd, J = 12.8, 5.4 Hz, 1H), 4.60-4.11 (m, 6H),4.11-3.71 (m, 1H), 3.56-3.44 (m, 1H), 3.34 (s, 3H), 3.283.06 (m, 1H),3.03-2.82 (m, 2H), 2.81-2.58 (m, 4H), 2.39- 1.61 (m, 15H), 1.61-1.29 (m,9H), 1.20 (d, J = 5.8 Hz, 6H) J120

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1S,4S)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]methyl]cyclohexyl]acetyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8-yl]formamido]-N- (naphthalen-1- ylmethyl) pentanediamidetrifluoroacetate  890.50 (300 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.49-8.24(m, 4H), 8.08-7.78 (m, 3H), 7.55-7.46 (m, 4H), 7.21 (s, 1H), 7.04-6.91(m, 2H), 6.88- 6.65 (m, 2H), 5.33 (dd, J = 12.7, 5.3 Hz, 1H), 5.33 (dd,J = 12.7, 5.3 Hz, 1H), 4.85-4.68 (m, 3H), 4.55- 4.34 (m, 2H), 4.34-4.10(m, 2H), 4.10-3.73 (m, 2H), 3.53-3.42 (m, 1H), 3.31 (s, 3H), 3.25-3.08(m, 1H), 3.02-2.85 (m, 2H), 2.81-2.55 (m, 5H), 2.47-2.39 (m, 1H), 2.36-2.06 (m, 4H), 2.06-1.59 (m, 4H), 1.58-1.25 (m, 11H) J121

(2S)-2-[[(2S,11S)- 11-amino-6-[5-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]pentyl]-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-N- (diphenylmethyl) pentanediamidetrifluoroacetate  867.75 (300 MHz, Methanol-d₄) δ 7.39- 7.14 (m, 10H),7.00 (s, 2H), 6.96- 6.87 (m, 3H), 6.15 (s, 1H), 5.32 (d, J = 11.8 Hz,1H), 5.21 (d, J = 10.8 Hz, 1H), 4.49 (dd, J = 9 0, 5.0 Hz, 1H), 4.15 (d,J = 10.8 Hz, 1H), 3.40 (s, 3H), 3.21-3.16 (m, 1H), 3.13-2.75 (m, 3H),2.69 (t, J = 7.4 Hz, 2H), 2.57 (t, J = 7.3 Hz, 2H), 2.48-2.07 (m, 4H),2.00-1.91 (m, 1H), 1.75-1.59 (m, 4H), 1.40-1.31 (m, 6H), 0.95-0.87 (m,1H) J122

(2S,4R)-1-[(2S)-2- (6-[5-[(2S)-2- [[(11S)-11-amino- 12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]fomiamido]-4- carbamoylbutoxy]- 2- chlorophenyl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1011.70 (300 MHz, DMSO-d₆) δ 9.04 (s, 1H),8.48 (s, 3H), 8.40 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.81(d, J = 8.9 Hz, 1H), 7.50-7.35 (m, 3H), 7.34-7.23 (m, 2H), 7.10 (d, J =7.3 Hz, 3H), 7.06-6.96 (m, 1H), 6.91-6.76 (m, 2H), 5.10 (d, J = 10.9 Hz,1H), 4.99-4.88 (m, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.20 (s, 1H), 3.97 (d,J = 8.0 Hz, 2H), 3.62- 3.60 (m, 2H), 3.54-3.38 (m, 2H), 3.18-3.14 (m,2H), 2.87-2.83 (m, 1H), 2.65-2.57 (m, 3H), 2.57-2.43 (m, 6H), 2.27-2.23(m, 1H), 2.17- 2.13 (m, 3H), 1.80-1.76 (m, 1H), 1.55-1.53 (m, 4H),1.43-1.22 (m, 9H), 0.95 (s, 9H) J123

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 4- chlorophenyl]hexanamido)-3.3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide 1011.67 (300 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.49-8.45 (m,2H), 8.39 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.45-7.40 (m,7H), 7.34-7.21 (m, 3H), 7.01 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 7.6 Hz,2H), 5.10 (d, J = 12.3 Hz, 1H), 4.54-4.50 (m, 1H), 4.33-4.22 (m, 3H),4.06-4.04 (m, 2H), 3.73-3.61 (m, 3H), 3.53-3.37 (m, 1H), 3.18-3.14 (m,2H), 3.04- 2.93 (m, 1H), 2.45 (s, 3H), 2.47- 2.38 (m, 3H), 2.24-2.09 (m,2H), 1.83-1.73 (m, 4H), 1.64-1.48 (m, 6H), 1.39 (d, J = 7.1 Hz, 3H),1.30- 1.21 (m, 5H), 0.94 (s, 9H) J124

(2S,4R)-1-[(2S)-2- (6-[3-[(3R-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylpentyl] phenyl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide  975.80 (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.58-8.43 (m,2H), 8.38 (d, J = 7.7 Hz, 1H), 8.17-7.99 (m, 1H), 7.77 (d, J = 9.1 Hz,1H), 7.41 (q, J = 8.4 Hz, 4H), 7.20-7.10 (m, 2H), 7.10-6.92 (m, 5H),6.73 (s, 2H), 5.09 (dd, J = 10.9, 3.0 Hz, 1H), 4.91 (t, J = 7.2 Hz, 1H),4.56-4.35 (m, 2H), 4.33-4.09 (m, 2H), 3.62- 3.58 (m, 4H), 3.52-3.29 (m,2H), 3.20-3.09 (m, 2H), 3.04-2.89 (m, 2H), 2.67 (m, 1H), 2.46 (s, 3H),2.33-2.18 (m, 2H), 2.15-1.98 (m, 6H), 1.87-1.41 (m, 8H), 1.37 (d, J =6.9 Hz, 4H), 1.33-1.17 (m, 2H), 0.93 (s, 9H) J125

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3- [(1r,4r)-4-[2-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]ethyl]cyclo- hexanecarbonyl]- octahydropyrrolo[1,2-a][1,5]diazocin-8- yl]formamido]-N- (diphenylmethyl) pentanediamidetrifluoroacetate  916.45 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.85 (dd, J= 10.8, 8.5 Hz, 1H), 8.38-8.27 (m, 1H), 7.31-7.21 (m, 10H), 7.16 (d, J =8.0 Hz, 2H), 7.04-6.97 (m, 2H), 6.87 (dd, 7 = 8.1, 1.6 Hz, 1H), 6.78 (s,1H), 6.11 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H),4.53-4.35 (m, 3H), 4.17 (s, 2H), 4.02-3.70 (m, 1H), 3.33 (s, 3H), 2.90(td, J = 13.3, 6.8 Hz, 1H), 2.77-2.53 (m, 9H), 2.26-1.98 (m, 2H),1.97-1.62 (m, 12H), 1.51 (q, J = 8.3 Hz, 3H), 1.28 (q, J = 10.7, 6.7 Hz,2H), 1.17-0.98 (m, 2H) J126

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3- [(1s,4s)-4-[2-[1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]ethyl]cyclo- hexanecarbonyl]- octahydropyrrolo[1,2-a][1,5]diazocin-8- yl]formamido]-N- (diphenylmethyl) pentanediamidetrifluoroacetate  916.40 (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.85 (t. J= 8.5 Hz, 1H), 8.38- 8.20 (m, 1H), 7.30-7.19 (m, 10H), 7.16 (d, J = 8.0Hz, 1H), 7.05-6.98 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 6.11(d, J = 8.4 Hz, 1H), 5.35 (dd, J = 12.8, 5.3 Hz, 1H), 4.52-4.37 (m, 2H),4.52-4.37 (m, 1H), 4.01-3.72 (m, 1H), 3.50- 3.38 (m, 1H), 3.34 (s, 3H),3.19- 3.05 (m, 1H), 3.03-2.85 (m, 2H), 2.78-2.55 (m, 8H), 2.37-2.28 (m,2H), 2.23-1.84 (m, 4H), 1.83-1.37 (m, 17H) J127

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 5- chlorophenyl]hexanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide 1011.35 (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.43 (s, 2H),8.35 (d, J = 7.7 Hz, 1H), 8.21 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 9.5 Hz,1H), 7.47-7.32 (m, 3H), 7.25 (s, 1H), 7.07 (d, J = 7.4 Hz, 2H),7.04-6.94 (m, 1H), 6.84 (s, 1H), 6.78 (d, J = 13.0 Hz, 2H), 6.70 (s,1H), 5.08 (d, J = 10.1 Hz, 1H), 4.92 (d, J = 7.4 Hz, 1H), 4.51 (d, J =9.3 Hz, 1H), 4.42 (t, J = 7.8 Hz, 1H), 4.32-4.25 (m, 1H), 4.23-4.17 (m,1H), 3.94 (s, 3H), 3.50-3.35 (m, 2H), 3.17-3.11 (m, 2H), 2.84 (d, J =16.1 Hz, 1H), 2.45 (s, 3H), 2.21 (d, J = 15.6 Hz, 3H), 2.15-2.04 (m,3H), 2.03-1.96 (m, 1H), 1.89-1.70 (m, 3H), 1.61- 1.44 (m, 5H), 1.37 (d,J = 7.0 Hz, 3H), 1.25 (d, J = 11.1 Hz, 5H), 0.92 (s, 9H) J128

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- methylphenyl]hexanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide  991.35 (400 MHz, DMSO-d₆) δ 9.09-9.06 (m, 1H), 8.54-8.51(m, 3H), 8.40 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.81 (d, J= 9.3 Hz, 1H), 7.48-7.42 (m, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.11-6.95(m, 4H), 6.75 (t, J = 7.5 Hz, 2H), 5.13-5.08 (m, 1H), 4.96-4.89 (m, 1H),4.54-4.49 (m, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.25-4.11 (m,2H), 4.05-4.01 (m, 1H), 3.94-3.83 (m, 2H), 3.67-3.59 (m, 3H), 3.44-3.39(m, 1H), 3.17-3.14 (m, 2H), 2.85 (dd, J = 17.1, 3.1 Hz, 1H), 2.56- 2.53(s, 2H), 2.47 (s, 3H), 2.36- 2.08 (m, 3H), 2.06 (s, 3H), 1.89- 1.71 (m,2H), 1.60-1.42 (m, 10H), 1.38 (d, J = 7.5 Hz, 3H), 1.35-1.29 (m, 1H),0.94 (s, 9H) J129

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2-amino- 4- carbamoylbutoxy]phenyl]hexanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]cycloprop yl]pyrrolidine-2-carboxamide hydrochloride  989.75 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H),8.81 (s, 1H), 8.50-8.45 (m, 3H), 8.24 (d, J = 8.2 Hz, 1H), 7.90 (d, J =9.2 Hz, 1H), 7.37-7.27 (m, 4H), 7.17 (t, J = 8.2 Hz, 1H), 7.07 (d, J =4.4 Hz, 2H), 7.04-6.96 (m, 1H), 6.81-6.71 (m, 4H), 5.10 (dd, J = 10.9,3.2 Hz, 1H), 4.62-4.52 (m, 1H), 4.39 (dd, J = 16.8, 8.7 Hz, 2H),4.22-4.17 (m, 2H), 4.03-3.95 (m, 2H), 3.97-3.85 (m, 2H), 3.70- 3.58 (m,3H), 3.52-3.37 (m, 1H), 3.15 (s, 2H), 2.87 (d, J = 17.0 Hz, 1H), 2.45(s, 3H), 2.45 (s, 2H), 2.33-2.17 (m, 2H), 2.14-2.10 (m, 3H), 2.05-1.96(m, 1H), 1.94-1.82 (m, 1H), 1.76 (s, 1H), 1.82-1.72 (m, 2H), 1.54 (s,2H), 1.55-1.52 (m, 1H), 1.32-1 16 (m, 4H), 1.16- 1.12 (m, 1H), 0.94 (s,9H) J130

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(11S)-11-amino- 12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 4- fluorophenyl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride [(M − 1)]⁻ = 993.15 (400 MHz, DMSO-d₆) δ 9.01(s, 1H), 8.47-8.34 (m, 3H), 8.26 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 9.1Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.26 (s,1H), 7.13-7.04 (m, 3H), 7.04-6.96 (m, 2H), 6.76 (s, 2H), 5.13-5.06 (m,1H), 4.91 (d, J = 7.1 Hz, 1H), 4.52 (d, J = 9.1 Hz, 1H), 4.45-4.41 (m,1H), 4.29 (s, 1H), 4.20 (s, 1H), 4.04 (d, J = 8.6 Hz, 1H), 3.73-3.57 (m,3H), 3.53-3.37 (m, 2H), 3.17- 3.13 (m, 2H), 2.90-2.86 (m, 1H), 2.46 (s,3H), 2.21-2.10 (m, 2H), 2.08 (s, 1H), 2.03-1.98 (m, 1H), 1.79 (d, J =19.1 Hz, 3H), 1.59- 1.49 (m, 4H), 1.41-1.34 (m, 4H), 1.25-1.20 (m, 7H),0.93 (s, 9H) J131

(2S)-2- ((5S,8S,10aR)-5- amino-3-(5-(3-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H- benzo[d]imidazol-5- yl)cyclobutyl)pentanoyl)-6- oxo- decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamido]-N- benzhydryl- pentancdiamide trifluoroacetate  916.35 (400MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.73 (dd, J = 8.6, 3.3 Hz, 1H), 8.26-8.08(m, 2H), 7.36-7.24 (m, 13H), 7.12-6.96 (m, 2H), 6.90 (dd, J = 21.6, 8.1Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.34 (dd, J= 12.9, 5.2 Hz, 1H), 4.43-4.28 (m, 3H), 4.19-3.40 (m, 6H), 3.34 (s, 3H),3.28-3.10 (m, 1H), 3.05-2.79 (m, 2H), 2.75- 2.61 (m, 3H), 2.48-1.47 (m,16H), 1.45-1.40 (m, 1H), 1.34-1.23 (m, 3H) J132

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[3-(5-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenyl] pentanediamide hydrochloride 990.60 (300 MHz, DMSO-d₆) δ 10.01 (s, 1H), 9.00 (s, 1H), 8.55-8.28 (m,5H), 7.76 (d, J = 9.1 Hz, 1H), 7.45- 7.36 (m, 7H), 7.23-6.91 (m, 4H),6.87 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 5.22-5.17 (m, 5H), 4.91 (t, J =7.1 Hz, 1H), 4.50 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.36-4.10 (m, 3H), 3.59 (s, 4H), 3.52- 3.37 (m, 1H), 3.16-3.11 (m, 2H),3.03-2.96 (m, 1H), 2.45 (s, 3H), 2.31-1.69 (m, 6H), 1.59-1.45 (m, 3H),1.37 (d, J = 7.0 Hz, 3H), 1.32- 1.18 (m, 3H), 0.92 (s, 9H) J133

(2S,4R)-1-[(2S)-2- [6-(3-[[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]phenyl)hexanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamide 977.55 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H),8.53- 8.41 (m, 4H), 8.14 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H),7.44- 7.38 (m, 4H), 7.25 (s, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.06 (t, J =6.6 Hz, 2H), 7.02-6.95 (m, 1H), 6.74 (d, J = 7.7 Hz, 2H), 6.69-6.66 (m,2H), 5.12 (dd, J = 10.9, 3.0 Hz, 1H), 4.54 (d, J = 9.4 Hz, 1H),4.48-4.32 (m, 4H), 4.27-4.12 (m, 2H), 3.83 (s, 1H), 3.74-3.60 (m, 2H),3.39 (q, J = 7.0 Hz, 3H), 3.16-3.12 (m, 2H), 2.78 (dd, J = 17.2, 3.0 Hz,1H), 2.45 (s, 3H), 2.34-1.98 (m, 5H), 1.98-1.81 (m, 1H), 1.73-1.43 (m,5H), 1.32-1.22 (m, 1H), 1.19 (d, J = 4.0 Hz, 2H), 1.10 (t, J = 7.0 Hz,4H), 0.93 (s, 9H) J134

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy] phenyl]pentanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2- carboxamidehydrochloride  963.40 (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.49 (d, J =16.8 Hz, 3H), 8.38 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.82(d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H),7.28 (s, 1H), 7.22-7.14 (m, 1H), 7.08 (d, J = 5.4 Hz, 2H), 7.05-6.96 (m,1H), 6.77- 6.73 (m, 3H), 5.12-5.08 (m, 1H), 4.91 (q, J = 7.3 Hz, 1H),4.52 (d, J = 9.2 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H),4.01-3.98 (m, 1H), 3.93-3.89 (m, 2H), 3.71-3.57 (m, 3H), 3.52-3.41 (m,1H), 3.45- 3.37 (m, 1H), 3.17-3.13 (m, 2H), 2.92-2.82 (m, 1H), 2.56-2.52(m, 2H), 2.47 (s, 3H), 2.33-2.20 (m, 1H), 2.21-1.96 (m, 3H), 1.87-1.70(m, 5H), 1.62-1.43 (m, 5H), 1.38 (d, J = 7.1 Hz, 3H), 0.94 (s, 9H) J135

(2S,4R)-1-[(2S)-2- (6-[5-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- methylphenyl]hexanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2- carboxamidehydrochloride  991.75 (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.59-8.55 (m,1H), 8.52 (d, J = 5.4 Hz, 2H), 8.40 (d, J = 7.8 Hz, 1H), 8.24 (d, J =8.3 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.49-7.32 (m, 4H), 7.30-7.28 (m,1H), 7.11-7.05 (m, 2H), 7.05-6.96 (m, 2H), 6.77- 6.75 (m, 1H), 6.70 (s,1H), 5.10- 5.08 (m, 1H), 4.92-4.90 (m, 1H), 4.56-4.48 (m, 1H), 4.43-4.41(m, 1H), 4.28-4.26 (m, 1H), 4.21-4.14 (m, 1H), 3.87-3.85 (m, 2H), 3.70-3.58 (m, 3H), 3.50-3.36 (m, 2H), 3.14-3.12 (m, 2H), 2.86-2.84 (m, 2H),2.45 (s, 3H), 2.28-2.26 (m, 2H), 2.21-1.97 (m, 7H), 1.87-1.66 (m, 3H),1.62-1.43 (m, 5H), 1.48- 1.46 (m, 2H), 1.35-1.32 (m, 4H), 0.94 (s, 9H)J136

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 5- methylphenyl]hexanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2- carboxamidehydrochloride  991.55 (400 MHz, DMSO-d₆) δ 9.07 (d, J = 1H), 8.53-8.50(m, J = 21.5 Hz, 2H), 8.39 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.2 Hz,1H), 7.78 (d, J = 9.3 Hz, 1H), 7.49-7.41 (m, 2H), 7.45- 7.32 (m, 2H),7.30 (s, 1H), 7.08 (d, J = 7.4 Hz, 2H), 7.00 (d, J = 8.3, 6.5 Hz, 1H),6.77 (s, 1H), 6.59 (s, 1H), 6.53 (d, J = 6.1 Hz, 2H), 5.10 (d, J = 10.9,3.0 Hz, 1H), 4.94-4.90 (m, 1H), 4.55-4.48 (m, 2H), 4.47- 4.39 (m, 2H),4.19 (d, J = 15.3, 10.4 Hz, 1H), 4.00-3.83 (m, 1H), 3.68-3.58 (m, 2H),3.62-3.58 (m, 2H), 3.57-3.50 (m, 7H), 3.48-3.37 (m, 2H), 3.17-3.13 (m,2H), 2.88- 2.84 (m, 1H), 2.45 (s, 3H), 2.51- 2.43 (m, 1H), 2.23 (s, 3H),2.20- 1.96 (m, 4H), 1.87-1.68 (m, 1H), 1.58-1.42 (m, 2H), 1.38 (d, J =7.0 Hz, 3H), 1.26-1.24 (m, 2H), 0.93 (s, 9H) J137

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 4- methylphenyl]hexanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2- carboxamidehydrochloride  991.35 (400 MHz, DMSO-d₆) δ 9.15 (d, J = 1.3 Hz, 1H),8.56-8.50 (m, 3H), 8.42 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H),7.79 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.42- 7.32 (m, 2H),7.06-7.02 (m, J = 6.7 Hz, 3H), 7.03-6.95 (m, 1H), 7.00 (s, 1H), 6.80 (s,1H), 6.73 (s, 1H), 6.69-6.62 (m, 1H), 5.12 (d, J = 10.9, 3.1 Hz, 1H),4.92 (d, J = 7.1 Hz, 1H), 4.51 (d, J = 9.4 Hz, 1H), 4.43 (d, J = 8.0 Hz,1H), 4.28 (s, 1H), 4.21-4.13 (m, 1H), 4.02 (s, 1H), 3.98-3.84 (m, 2H),3.69-3.56 (m, 7H), 3.49-3.36 (m, 3H), 3.17- 3.13 (m, 2H), 2.87-2.83 (m,1H), 2.48-2.46 (m, 1H), 2.45 (s, 3H), 2.32-1.98 (m, 6H), 1.86-1.69 (m,4H), 1.62-1.45 (m, 3H), 1.38- 1.34 (m, 3H), 1.30-1.21 (m, 1H), 0.93 (s,9H) J138

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- fluorophenyl]hexanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2- carboxamidehydrochloride  995.40 (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.54 (d, J =17.3 Hz, 3H), 8.40 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.79(d, J = 9.3 Hz, 1H), 7.49-7.32 (m, 4H), 7.30 (s, 1H), 7.08 (s, 2H),7.04-6.96 (m, 2H), 6.84-6.71 (m, 2H), 5.12-5.08 (m, 1H), 4.93-4.89 (m,1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H),4.18 (s, 1H), 4.00-3.82 (m, 2H), 3.69-3.57 (m, 6H), 3.49-3.36 (m, 1H),3.15 (s, 2H), 2.87-2.83 (m, 1H), 2.54 (d, J = 7.4 Hz, 1H), 2.47 (s, 3H),2.31- 2.06 (m, 2H), 2.06-1.97 (m, 1H), 1.87-1.79 (m, 1H), 1.82-1.71 (m,4H), 1.60 (s, 1H), 1.55-1.51 (m, 4H), 1.50-1.42 (m, 1H), 1.38 (d, J =7.0 Hz, 3H), 1.30-1.26 (m, 1H), 0.93 (s, 9H) J139

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 5- fluorophenyl]hexanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2- carboxamidehydrochloride  995.40 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.46 (d, J =16.0 Hz, 2H), 8.39 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.80(d, J = 9.3 Hz, 1H), 7.48-7.37 (m, 3H), 7.38 (s, 1H), 7.28 (s, 1H), 7.08(d, J = 7.6 Hz, 2H), 7.05-6.96 (m, 1H), 6.79 (s, 1H), 6.65-6.57 (m, 3H),5.11- 5.07 (m, 1H), 4.93-4.89 (m, 1H), 4.72-4.57 (m, 1H), 4.55-4.48 (m,1H), 4.42 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.20 (d, J = 9.4 Hz, 1H),4.04-3.88 (m, 2H), 3.76-3.57 (m, 3H), 3.53-3.37 (m, 2H), 3.17-3.13 (m,2H), 2.87-2.83 (m, 1H), 2.54 (s, 1H), 2.46 (s, 3H), 2.17-2.13 (m, 7H),1.85-1.70 (m, 2H), 1.58-1.51 (m, 5H), 1.48-1.34 (m, 3H), 1.30- 1.21 (m,2H), 0.93 (s, 9H) J140

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)-2-methylphenyl] pentanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1005.60 (400 MHz, DMSO-d₆) δ 9.03 (s, 1H),8.60-8.30 (m, 4H), 8.01 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H),7.47-7.35 (m, 4H), 7.26-7.11 (m, 1H), 7.11-6.95 (m, 5H), 6.74 (s, 1H),5.13 (dd, J = 11.0, 3.1 Hz, 1H), 4.92 (t, J = 7.2 Hz, 1H), 4.54- 4.52(m, 2H), 4.43-4.41 (m, 1H), 4.37 (s, 2H), 4.28 (s, 1H), 4.22- 4.16 (m,1H), 3.86-3.74 (m, 1H), 3.64-3.60 (m, 2H), 3.52-3.35 (m, 2H), 3.17-3.13(m, 2H), 2.90-2.84 (m, 1H), 2.57-2.54 (m, 3H), 2.46 (s, 3H), 2.38-2.27(m, 1H), 2.24- 1.96 (m, 5H), 1.83-1.75 (m, 2H), 1.64-1.43 (m, 6H), 1.38(d, J = 7.1 Hz, 3H), 1.29-1.24 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H), 0.94(s, 9H), 0.89-0.81 (m, 1H) J141

(2S,4R)-1-[(2S)-2- [6-(3-[[(2R,3S)-3- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]phenyl)hexanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] pyrrolidine-2- carboxamidehydrochloride  991.75 (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.56-8.50 (m,5H), 8.39 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.79 (d, J =9.3 Hz, 1H), 7.48- 7.37 (m, 6H), 7.22-6.96 (m, 7H), 6.75 (d, J = 7.6 Hz,2H), 6.70-6.67 (m, 2H), 5.13 (dd, J = 10.9, 3.0 Hz, 1H), 4.92 (t, J =7.2 Hz, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.47-4.37 (m, 1H), 4.28 (s, 1H),4.18-4.16 (m, 1H), 3.86-3.82 (m, 1H), 3.16-3.12 (m, 5H), 2.78 (d, J =16.6 Hz, 1H), 2.46 (s, 3H), 2.34-1.94 (m, 8H), 1.92-1.60 (m, 2H),1.56-1.47 (m, 4H), 1.30-1.24 (m, 2H), 1.19 (d, J = 6.1 Hz, 3H), 0.93 (s,9H) J142

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[[3-(5-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4-methyl-1,3-(thiazol- 5- yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]pentyl) phenyl]methyl]pentanediamide hydrochloride 1004.65 (400 MHz, DMSO-d6) δ 9.08 (s, 1H),8.51 (d, J = 5.4 Hz, 2H), 8.44 (d, J = 6.9 Hz, 2H), 8.40 (d, J = 7.8 Hz,1H), 7.81 (d, J = 9.3 Hz, 1H), 7.47-7.43 (m, 2H), 7.39 (d, J = 8.4 Hz,2H), 7.18 (t, J = 7.8 Hz, 1H), 7.11-6.98 (m, 7H), 6.82-6.79 (m, 1H),4.93 (q, J = 7.0 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz,1H), 4.31-4.14 (m, 6H), 3.48- 3.36 (m, 2H), 3.13 (d, J = 6.4 Hz, 2H),2.95 (d, J = 17.2 Hz, 1H), 2.47 (s, 3H), 2.25 (dt, J = 15.3, 7.8 Hz,2H), 2.17-1.99 (m, 6H), 1.92 (s, 1H), 1.80 (ddd, J = 13.0, 8.6, 4.8 Hz,2H), 1.57-1.46 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H), 1.28- 1.21 (m, 3H),1.10 (t, J = 7.0 Hz, 1H), 0.93 (s, 9H) J143

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]phenyl]pentanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]methyl] pyrrolidine-2- carboxamidehydrochloride  949.55 (300 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.61-8.56 (m,1H), 8.49-8.43 (m, 3H), 8.26 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 9.4 Hz,1H), 7.46-7.35 (m, 4H), 7.29 (s, 1H), 7.22-7.12 (m, 1H), 7.12-6.93 (m,3H), 6.85- 6.68 (m, 4H), 5.09 (d, J = 10.6 Hz, 1H), 4.58-4.53 (m, 2H),4.43-4.39 (m, 4H), 4.37-4.32 (m, 2H), 4.26- 4.16 (m, 2H), 4.05-3.82 (m,2H), 3.67-3.63 (m, 2H), 3.49-3.38 (m, 3H), 2.89-2.73 (m, 1H), 3.18-3.12(m, 2H), 2.45 (s, 3H), 2.25-1.98 (m, 4H), 1.94-1.68 (m, 1H), 1.60- 1.48(m, 6H), 0.94 (s, 9H) J144

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]][ trideca- 4(13),5,7-trien-2- yl]formamido]-N-[[3-(5-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-([[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl] carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl) phenyl]methyl] pentanediamidehydrochloride  990.60 (400 MHz, DMSO-d₆) δ 9.06 (s, 1 H), 8.58 (t, J =6.0 Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.43 (d, J = 6.9 Hz, 1H), 7.86(d, J = 9.3 Hz, 1H), 7.51-7.34 (m, 4H), 7.26-7.13 (m, 1H), 7.10-7.02 (m,4H), 6.80(s, 1H), 5.18 (dd, J = 10.9, 3.0 Hz, 1H), 4.61-4.51 (m, 1H),4.49-4.39 (m, 2 H), 4.34 (d, J = 11.8 Hz, 1H), 4.22- 4.20 (m, 4H),3.73-3.59 (m, 2H), 3.49-3.41 (m, 1H), 3.40 (d, J = 1.0 Hz, 1H), 3.13 (d,J = 6.6 Hz, 1H), 3.00-2.90 (m, 1H), 2.46 (s, 3H), 2.29-2.25 (m, 2H),2.17-1.99 (m, 4 H), 1.92-1.89 (m, 1H), 1.85-1.72 (m, 1H), 1.53-1.46 (m,4H), 1.27- 1.23 (m, 2H), 0.93 (s, 9H). J145

(2S,4R)-1-[(2S)-2- [(1-[3-[4-([[2R,3S)- 3-[[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl]phenyl]propyl] cyclopropyl) formamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl-1,3-thiazol- 5- yl)phenyl]methyl]pyrrolidine-2- carboxamide hydrochloride 1003.75 (400 MHz, Methanol-d₄)δ 9.64 (d, J = 29.4 Hz, 1H), 8.11 (s, 1H), 7.61-7.47 (m, 3H), 7.22 (d, J= 7.9 Hz, 2H), 7 18-6.99 (m, 5H), 5.19 (dd, 7 = 10.9, 3.5 Hz, 1H), 4.71(s, 1H), 4.69-4.58 (m, 1H), 4.58 (d, J = 3.7 Hz, 1H), 4.58-4.48 (m, 3H),4.48-4.39 (m, 1H), 4.42-4.28 (m, 1H), 4.20 (d, J = 13.5 Hz, 1H),4.07-3.99 (m, 1H), 3.91-3.71 (m, 2H), 3.62 (s, 2H), 3.60-3.46 (m, 1H),3.26 (s, 3H), 3.11-2.99 (m, 1H), 2.66 (s, 2H), 2.57 (d, J = 6.4 Hz, 3H),2.42-2.23 (m, 1H), 2.27 (s, 3H) ,2.15-1.96 (m, 1H), 1.81 (s, 3H), 1.31(s, 1H), 1.26-1.17 (m, 3H), 1.17-1.09 (m, 1H), 1.01 (d, J = 10.2 Hz,9H), 0.96-0.85 (m, 1H), 0.65 (s, 2H) J147

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11s)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)-3-fluorophenyl]- pentanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1009.55 (400 MHz, DMSO-d₆) δ 9.04 (s, 1H),8.52-8.47 (d, J = 5.3 Hz, 3H), 8.39 (d, J = 7.8 Hz, 1H), 8.03 (d, J =9.1 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.47-7.36 (m, 4H), 7.24 (t, J =7.9 Hz, 1H), 7.09-7.07 (m, 2H), 7.04-6.97 (m, 2H), 6.94 (d, J = 7.7 Hz,1H), 6.73 (s, 1H), 5.12 (dd, J = 11.0, 3.1 Hz, 1H), 4.96-4.89 (m, 1H),4.56-4.42 (m, 10H), 4.28 (s, 1H), 4.23-4.13 (m, 1H), 3.85-3.72 (m, 1H),3.62-3.60 (m, 1H), 3.52- 3.36 (m, 2H), 3.17-3.13 (m, 2H), 2.88-2.83 (m,1H), 2.58 (t, J = 7.2 Hz, 1H), 2.47 (s, 3H), 2.38-1.95 (m, 3H),1.83-1.74 (m, 1H), 1.64- 1.41 (m, 7H), 1.38 (d, J = 7.1 Hz, 3H), 1.09(d, J = 6.1 Hz, 3H), 0.94 (s, 9H) J148

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11s)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)-3-methylphenyl] pentanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride [(M + Na)]⁺ = 1027.80 (400 MHz, DMSO-d₆) δ9.21 (s, 1H), 8.59-8.50 (m, 3H), 8.41 (dd, J = 7.9, 2.3 Hz, 1H), 8.02(dd, J = 24.9, 8.8 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.48-7.44 (m, 2H),7.40 (d, J = 8.4 Hz, 2H), 7.29-7.24 (m, 1H), 7.13-7.06 (m, 3H),7.02-6.96 (m, 2H), 6.93-6.89 (m, 1H), 6.67- 6.64 (m, 4H), 5.11 (ddd, J =22.5, 11.8, 3.1 Hz, 1H), 4.95-4.88 (m, 1H), 4.75 (s, 1H), 4.52 (d, J =9.2 Hz, 1H), 4.46-4.40 (m, 2H), 4.38- 4.33 (m, 1H), 4.29-4.27 (m, 1H),4.16 (dd, J = 13.0, 7.9 Hz, 1H), 3.82-3.73 (m, 1H), 3.52-3.35 (m, 4H),3.15 (d, J = 13.2 Hz, 2H), 2.94-2.79 (m, 1H), 2.48 (s, 3H), 2.35-2.26(m, 3H), 2.22-2.11 (m, 4H), 2.08-2.00 (m, 2H), 1.81-1.77 (m, 2H),1.61-1.59 (m, 1H), 1.56- 1.48 (m, 4H), 1.38 (d, J = 7.0 Hz, 3H),1.12-1.07 (m, 3H), 0.94 (s, 9H) J149

(2S,4R)-1-[(2S)-2- [5-[4-([[(2R,3S)-3- [[(2S,11s)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-5- carbamoylpentan-2- yl]oxy]methyl)phenyl] pentanamido]-3,3- dimethylbutanoyl]- 4-hydroxy-N-[4-(4-methyl-1,3- thiazol-5- yl)phenoxy] pyrrolidine-2- carboxamidehydrochloride 1001.55 (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.49-8.37 (m,2H), 7.99 (dd, J = 16.2, 9.2 Hz, 1H), 7.39-7.34 (m, 2H), 7.31-7.25 (m,2H), 7.21-7.13 (m, 3H), 7.12-7.06 (m, 4H), 7.04- 6.99 (m, 1H), 6.75 (s,1H), 5.13 (dd, J = 11.0, 3.1 Hz, 1H), 4.57- 4.54 (m, 1H), 4.39 (d, J =6.0 Hz, 3H), 4.20 (d, J = 8.5 Hz, 1H), 3.69 (d, J = 2.5 Hz, 2H),3.49-3.44 (m, 2H), 3.42-3.39 (m, 2H), 3.37 (d, J = 7.0 Hz, 1H),3.18-3.13 (m, 2H), 2.90-2.83 (m, 1H), 2.52-2.55 (s, 1H) 2.43 (s, 3H),2.17 (d, J = 6.2 Hz, 2H), 2.13-2.06 (m, 3H), 2.01- 1.96 (m, 2H),1.80-1.75 (m, 1H), 1.56-1.48 (m, 5H), 1.24 (s, 1H), 1.15-1.07 (m, 7H),0.93 (s, 9H) J150

(2S)-2- [[(5S,8S,10aR)-5- amino-3-(4-[3-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]cyclobutyl]butanoyl)-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-N-(diphenylmethyl) pentanediamide trifluoroacetate  902.35 Used in thenext step without further purification J151

(2S)-2-[[(2S,11S)- 11-amino-6-[6-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]hexyl]-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-N- (diphenylmethyl) pentanediamide 881.25 (400 MHz, DMSO-d₆) δ 8.79 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.0Hz, 1H), 7.36-7.18 (m, 12H), 7.04- 6.96 (m, 2H), 6.92-6.81 (m, 3H), 6.78(s, 1H), 6.08 (d, J = 8.3 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 5.10(dd, J = 11.0, 3.2 Hz, 1H), 4.39-4.24 (m, 1H), 3.75 (d, J = 9.7 Hz, 1H),3.31 (s, 3H), 3.06- 3.01 (m, 2H), 2.96-2.80 (m, 2H), 2.75-2.56 (m, 5H),2.48-2.46 (m, 3H), 2.19-1.72 (m, 7H), 1.68-1.45 (m, 4H), 1.35-1.32 (m,5H) J152

(2R)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1s,4s)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl)methyl]cyclohexyl] acetyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8-yl]formamido]-N- [(4- methanesulfonyl- phenyl)methyl] pentanediamidetrifluoroacetate  918.30 (400 MHz, DMSO-d₆) δ 11.03- 10.94 (m, 1H),8.70-8.62 (m, 1H), 8.60-8.51 (m, 1H), 8.48-8.25 (m, 1H), 8.21 (d, J =6.6 Hz, 1H), 7.91- 7.82 (m, 2H), 7.54-7.48 (m, 2H), 7.30-7.22 (, 1H),7.06-6.95 (m, 2H), 6.88-6.71 (m, 2H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H),4.52-4.28 (m, 4H), 4.28-4.04 (m, 2H), 4.04- 3.39 (m, 3H), 3.32 (s, 3H),3.21- 3.13 (m, 5H), 2.93-2.86 (m, 1H), 2.77-2.53 (m, 4H), 2.45-2.30 (m,2H), 2.30-2.05 (m, 4H), 2.01-1.92 (m, 4H), 1.89-1.54 (m, 4H), 1.49- 1.25(m, 8H) J153

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2- fluorophenyl] butanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride  990.35 (400 MHz, DMS-d₆) δ9.05-9.03 (m, 1H), 8.50-8.46 (m, 1H), 8.40 (d, J = 7.8 Hz, 1H),8.37-8.32 (m, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 9.3 Hz, 1H),7.46-7.43 (m, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.26- 7.24 (m, 1H),7.04-7.00 (m, 2H), 6.85-6.75 (m, 2H), 4.93-4.91 (m, 1H), 4.53 (d, J =9.3 Hz, 2H), 4.45- 4.34 (m, 2H), 4.28-4.23 (m, 3H), 4.08-3.98 (m, 3H),3.93-3.90 (m, 1H), 3.77 (d, J = 14.9 Hz, 1H), 3.61 (d, J = 4.3 Hz, 2H),3.54-3.45 (m, 1H), 3.42-3.35 (m, 1H), 3.27- 3 24 (m, 1H), 3 15 (d, J =70 Hz, 1H), 2.59-2.56 (m, 2H), 2.47 (s, 3H), 2.22-2.10 (m, 7H),2.06-1.99 (m, 1H), 1.88-1.67 (s, 9H), 1.38 (d, J = 7.0 Hz, 3H),1.12-1.10 (m, 1H), 0.94 (s, 9H) J154

(2S)-2-[[(2S,11S)- 11-amino-6-[6[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]hexyl]-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4.13]]- trideca-4(13),5,7-trien-2- yl]]formamido]-N- [(4- isopropylphenyl) methyl]pentanediamide hydrochloride  847.10 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),8.53-8.39 (m, 4H), 7.33 (s, 1H), 7.18-7.10 (m, 4H), 7.05-6.98 (m, 2H),6.93 (s, 1H), 6.90-6.84 (m, 2H), 6.80 (s, 1H), 5.36-5.33 (m, 1H),5.19-5.14 (m, 1H), 4.26- 4.14 (m, 4H), 3.46-3.36 (m, 1H), 3.32 (s, 3H),3.12-3.08 (m, 2H), 2.96-2.80 (m, 3H), 2.75-2.67 (m, 1H), 2.65-2.58 (m,4H), 2.49-2.46 (m, 1H), 2.23-2.20 (m, 1H), 2.14- 2.10 (m, 2H), 2.02-2.00(m, 2H), 1.92-1.88 (m, 1H), 1.80-1.78 (m, 1H), 1.57-1.54 (m, 4H),1.36-1.30 (m, 4H), 1.17 (d, J = 6.9 Hz, 6H) J155

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2- chlorophenyl] pentanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-(4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride 1020.45 (400 MHz, DMSO-d₆) δ9.12 (s, 1H), 8.56 (s, 2H), 8.43 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.2Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.49-7.43 (m, 2H), 7.40 (d, 7 = 8.3Hz, 2H), 7.28 (s, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.99 (dd, J = 8.3, 1.4Hz, 1H), 6.95-6.88 (m, 1H), 6.78 (s, 1H), 4.92 (p, J = 7.2 Hz, 1H), 4.52(d, J = 9.3 Hz, 1H), 4.48-4.34 (m, 2H), 4.28 (s, 2H), 4.11-4.00 (m, 3H),3.93 (d, J = 8.7 Hz, 1H), 3.78 (s, 1H), 3.71-3.57 (m, 4H), 3.53-3.36 (m,1H), 3.31-3.15 (m, 1H), 2.71- 2.67 (m, 2H), 2.48 (s, 3H), 2.40- 2.26 (m,1H), 2.19-2.15 (m, 6H), 2.11 (s, 1H), 2.08-2.00 (m, 1H), 1.98-1.85 (m,3H), 1.85-1.66 (m, 3H), 1.61-1.43 (m, 6H), 1.38 (d, J = 7.0 Hz, 3H),0.94 (s, 9H) J156

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1s,4s)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8-yl]formamido]-N- (diphenylmethyl) pentanediamide trifluoroacetate 916.80 (300 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.87 (d, J = 8.4 Hz, 1H),8.55- 8.18 (m, 4H), 7.38-7.25 (m, 12H), 7.10-6.92 (m, 2H), 6.90-6.71 (m,2H), 6.12 (d, J = 8.2 Hz, 1H), 5.36 (dd, J = 12.7, 5.4 Hz, 1H), 4.57-4.33 (m, 3H), 4.23-4.17 (m, 1H), 4.13-3.74 (m, 2H), 3.40 (q, J = 7.0 Hz,1H), 3.33 (s, 3H), 3.05-2.86 (m, 1H), 2.80-2.57 (m, 4H), 2.42- 2.06 (m,4H), 2.06-1.65 (m, 9H), 1.46-1.32 (m, 9H), 1.11 (t, J = 7.0 Hz, 1H) J157

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- y]|formamido]-4- carbamoylbutoxy]- 2-fluoro-5-methylphenyl] butanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  981.45 (300 MHz, DMSO-d₆) δ 9.04 (s, 1H),8.57-8.45 (m, 3H), 8.38 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H),7.86 (d, J = 9.2 Hz, 1H), 7.47- 7.35 (m, 4H), 7.09-6.94 (m, 4H), 6.81(d, J = 7.8 Hz, 1H), 6.60 (d, J = 6.1 Hz, 1H), 5.10-5.07 (m, 2H), 4.91(t, J = 7.2 Hz, 1H), 4.56-4.49 (m, 1H), 4.42 (t, J = 7.9 Hz, 1H),4.30-4.25 (m, 1H), 4.22-4.12 (m, 1H), 4.04-3.87 (m, 4H), 3.62-3.59 (m,2H), 3.51-3.34 (m, 2H), 3.18- 3.09 (m, 2H), 2.91-2.80 (m, 1H), 2.45 (s,3H), 2.32-2.25 (m, 1H), 2.22 (s, 3H), 2.19-2.08 (m, 3H), 2.07-1.94 (m,2H), 1.87-1.63 (m, 6H), 1.37 (s, 3H), 0.94 (s, 9H) J158

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2-fluoro-5- methylphenyl] pentanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride 1018.40 ¹H NMR(400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.69-8.55 (m, 2H), 8.50-8.39 (m, 2H),8.26 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.49-7.38 (m, 5H),6.85-6.78 (m, 1H), 6.61 (d, J = 5.8 Hz, 1H), 4.92 (p, J = 7.2 Hz, 1H),4.54-4.35 (m, 4H), 4.32-4.17 (m, 3H), 4.10 (d, J = 13.7 Hz, 1H),4.05-3.94 (m, 2H), 3.93-3.84 (m, 1H), 3.80-3.69 (m, 1H), 3.68-3.53 (m,3H), 3.51-3.32 (m, 1H), 3.30-3.09 (m, 2H), 2.49 (s, 3H), 2.22 (s, 3H),2.20-2.07 (m, 7H), 2.06-1.98 (m, 1H), 1.97-1.63 (m, 8H), 1.53-1.42 (m,5H), 1.37 (s, 3H), 0.93 (s, 9H) J159

(2S,4R)-1-[(2S)-2- (5-[4-[(4R)-4- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-6- carbamoylhexyl] phenyl]pentanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride 975.55 ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.39 (d, J = 7.9 Hz,4H), 7.91 (dd, J = 60.7, 9.1 Hz, 2H), 7.48-7.36 (m, 4H), 7.13-7.02 (m,7H), 6.68 (s, 1H), 5.05 (d, J = 10.8 Hz, 1H), 4.96-4.89 (m, 1H), 4.52(d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.24 (d, J = 35.5 Hz,2H), 3.72-3.61 (m, 2H), 3.52-3.33 (m, 2H), 3.15 (s, 2H), 2.46 (s, 5H),2.37-1.93 (m, 10H), 1.79 (s, 1H), 1.63-1.59 (m, 2H), 1.51-1.22 (m, 12H),0.94 (s, 9H) J160

(2S,4R)-1-[(2S)-2- (6-[6-[(1S)-1- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-3- carbamoylpropyl] pyridin-3-yl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide [(M − H)]⁻ = 946.95 (300 MHz, DMSO-d₆) δ 9.18-9.17 (d, J =7.4 Hz, 1H), 9.05 (s, 1H), 8.72-8.71 (d, J = 2.1 Hz, 1H), 8.60-8.54 (m,3H), 8.50-8.39 (m, 2H), 7.98-7.95 (d, J = 8.4 Hz, 1H), 7.83-7.80 (d, J =9.3 Hz, 1H), 7.48-7.32 (m, 4H), 7.07-7.05 (m, 2H), 7.01-6.93 (m, 1H),6.83 (s, 1H), 5.17-5.13 (dd, J = 11.0, 3.5 Hz, 1H), 4.96-4.88 (m, 2H),4.53- 4.50 (d, J = 9.3 Hz, 1H), 4.47-4.41 (m, 1H), 4.29 (s, 1H),4.24-4.17 (m, 1H), 3.64-3.61 (d, J = 4.1 Hz, 2H), 3.52-3.45 (m, 1H),3.14-3.12 (m, 2H), 3.03-2.99 (t, J = 7.8 Hz, 2H), 2.84-2.79 (dd, J =17.3, 3.3 Hz, 1H), 2.47 (s, 3H), 2.31-2.24 (m, 2H), 2.20-2.12 (m, 2H),2.08 (s, 4H), 2.06-1.94 (m, 2H), 1.84- 1.67 (m, 3H), 1.58-1.47 (m, 2H),1.39-1.37 (d, J = 7.0 Hz, 3H), 1.33-1.22 (m, 2H), 0.93 (s, 9H) J161

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2-[[(2S)- 1-[(2S)-2-amino-4-methylpentanoyl]- pyrrolidin-2- yl]formamido]-4- carbamoylbutoxy]- 2-chlorophenyl] pentanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  979.45 (400 MHz, DMSO-d₆) δ 9.08 (s, 1H),8.42 (d, J = 7.8 Hz, 1H), 8.25 (s, 2H), 8.06 (d, J = 8.1 Hz, 1H), 7.85(d, J = 9.2 Hz, 1H), 7.45 (d, J = 2.3 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H),7.22-7.18 (m, 2H), 7.06-6.95 (m, 1H), 6.91 (dd, J = 7.7. 1.3 Hz, 1H),6.79 (s, 1H), 4.92 (p, J = 7.2 Hz, 1H), 4.52 (d, J = 9.4 Hz, 1H),4.49-4.33 (m, 2H), 4.28 (s, 1H), 4.08 (s, 3H), 4.05-3.96 (m, 1H),3.96-3.84 (m, 1H), 3.80-3.70 (m, 2H), 3.70-3.57 (m, 2H), 3.53-3.41 (m,1H), 3.45-3.37 (m, 1H), 2.69 (s, 3H), 2.58-2.55 (m, 1H), 2.47 (s, 3H),2.33-2.29 (m, 1H), 2.19-2.15 (m, 2H), 2.09-1.94 (m, 2H), 1.90- 1.70 (m,4H), 1.63-1.47 (m, 6H), 1.38 (d, J = 7.1 Hz, 3H), 0.94 (s, 15H) J162

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2-[[(2S)- 1-[(2S)-2-amino-4-methylpentanoyl] pyrrolidin-2- yl]formamido]-4- carbamoylbutoxy]- 2-chlorophenyl] butanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  965.45 (400 MHz, DMSO-d₆) δ 9.09 (s, 1H),8.42 (d, J = 7.7 Hz, 1H), 8.30- 8.21 (m, 2H), 8.05 (d, J = 8.0 Hz, 1H),7.89 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz,2H), 7.27-7.17 (m, 2H), 6.99 (d, J = 8.3, 1H), 6.89 (d, J = 7.6, 1H),6.79 (s, 1H), 4.93-4.89 (m, 1H), 4.55-4.50 (m, 1H), 4.43 (t, J = 8.0 Hz,1H), 4.38-4.34 (m, 1H), 4.29-4.27 (m, 1H), 4.08-4.04 (m, 2H), 4.04-3.97(m, 1H), 3.94-3.91 (m, 1H), 3.76-3.72 (m, 1H), 3.62- 3.59 (m, 2H),3.46-3.39 (m, 1H), 2.67 (t, J = 7.4 Hz, 2H), 2.47 (s, 3H), 2.32-2.28 (m,1H), 2.21-2.13 (m, 3H), 2.10-1.93 (m, 3H), 1.80- 1.71 (m, 9H), 1.58-1.54(m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 0.99-0.90 (m, 15H) J163

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido)-4-carbamoylbutoxy]- 2- chlorophenyl] butanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride 1006.11 (400 MHz, DMSO-d₆) δ9.11 (d, J = 2.4 Hz, 1H), 8.59 (s, 2H), 8.43 (d, J = 8.1 Hz, 2H),8.26-8.19 (m, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.50 (s, 2H), 7.45 (d, J =8.3 Hz, 2H), 7.25 (s, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.03-6.97 (m, 1H),6.89 (d, J = 7.5 Hz, 1H), 4.92 (p, J = 6.9 Hz, 1H), 4.65 (dd, J = 6.6,2.4 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.46-4.35 (m, 2H), 4.34-4.17 (m,3H), 4.04 (d, J = 17.0 Hz, 1H), 3.93 (d, J = 9.3 Hz, 1H), 3.87-3.64 (m,2H), 3.60 (q, J = 3.4 Hz, 2H), 3.57-3.55 (m, 2H), 3.54-3.43 (m, 1H),3.42- 3.33 (m, 1H), 3.31-3.10 (m, 1H), 2.70-2.63 (m, 2H), 2.47 (s, 3H),2.31-2.28 (m, 2H), 2.17-2.13 (m, 6H), 2.11-1.97 (m, 2H), 1.96-1.64 (m,3H), 1.48-1.41 (m, 2H), 1.37- 1.31 (m, 3H), 1.23-1.19 (m, 1H), 0.94 (s,9H) J164

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1s,4s)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5-yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8-yl]formamido]-N- (diphenylmethyl) pentanediamide trifluoroacetate 916.40 (300 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.87 (d, J = 8.4 Hz, 1H),8.49- 8.23 (m, 4H), 7.43-7.18 (m, 12H), 7.05-6.93 (m, 2H), 6.91-6.69 (m,2H), 6.13 (d, J = 8.2 Hz, 1H), 5.36 (dd, J = 12.7, 5.4 Hz, 1H), 4.53-4.42 (m, 3H), 4.31-4.11 (m, 1H), 4.09-3.77 (m, 1H), 3.34 (s, 3H),3.29-2.81 (m, 3H), 2.80-2.57 (m, 4H), 2.40-1.61 (m, 13H), 1.53- 1.30 (m,9H) J165

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- chlorophenyl]pentanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  997.35 (300 MHz, DMSO-d₆) δ 9.19 (d, J = 4.8Hz, 1H), 8.62 (s, 3H), 8.46 (d, J = 7.7 Hz, 1H), 8.36 (d, J = 7.0 Hz,1H), 7.86 (d, J = 9.2 Hz, 1H), 7.60 (s, 3H), 7.26 (s, 2H), 7.20 (t, J =7.9 Hz, 1H), 7.09-7.03 (m, 3H), 6.99 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H),5.12 (d, J = 10.5 Hz, 1H), 4.98-4.87 (m, 1H), 4.53 (d, J = 9.1 Hz, 1H),4.45 (t, J = 8.1 Hz, 1H), 4.29 (s, 1H), 4.16 (s, 1H), 4.04 (d, J = 7.0Hz, 2H), 4.00-3.96 (m, 1H), 3.53-3.31 (m, 2H), 3.18-3.12 (m, 3H),2.99-2.95 (m, 1H), 2.72- 2.68 (m, 3H), 2.47 (s, 3H), 2.31 (s, 2H),2.21-2.17 (m, 1H), 2.11-1.98 (m, 2H), 1.95-1.85 (m, 1H), 1.78 (s, 3H),1.57-1.53 (m, 5H), 1.43- 1.34 (m, 3H), 0.95 (s, 9H) J166

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 5-chloro-2-fluorophenyl] hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1029.25 (400 MHz, DMSO-d₆) δ 9.03 (d, J = 5.4Hz, 1H), 8.48 (s, 2H), 8.40 (d, J = 7.7 Hz, 1H), 8.30 (d, J = 7.3 Hz,1H), 7.81 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.38 (d, J =8.1 Hz, 2H), 7.30 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 4.7Hz, 2H), 7.01 (d, J = 7.3 Hz, 1H), 6.93 (m, 1H), 6.80 (s, 1H), 5.09 (d,J = 11.0 Hz, 1H), 4.91 (q, J = 7.3 Hz, 1H), 4.42 (t, J = 8.0 Hz, 3H),4.30-4.26 (m, 1H), 4.20 (d, J = 7.9 Hz, 1H), 4.09-4.03 (m, 1H), 3.98-3.95 (m, 2H), 3.47-3.34 (m, 2H), 3.15-3.13 (m, 2H), 2.87 (d, J = 16.5Hz, 1H), 2.46 (s, 3H), 2.30- 2.18 (m, 3H), 2.15-2.11 (m, 3H), 2.03-1.99(m, 1H), 1.87-1.67 (m, 4H), 1.54-1.45 (m, 5H), 1.38 (d, J = 7.2 Hz, 3H),1.29-1.20 (m, 3H), 0.93 (s, 9H) J167

(2S)-2-[[(2S,11S)- 11-amino-6-[(4-[[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]methyl] cyclohexyl)methyl]-12-oxo-1- azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formainido]-N- (diphenylmethyl) pentanediamidetrifluoroacetate  907.55 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.83 (d, J= 8.8 Hz, 1H), 8.37- 8.33 (m, 3H), 7.34-7.22 (m, 11H), 7.06-6.95 (m,2H), 6.92-6.90 (m, 1H), 4.22-4.20 (m, 1H), 3.32 (d, J = 5.2 Hz, 2H),3.12-3.10 (m, 1H), 2.91-2.86 (m, 2H), 2.62 (d, J = 9.7 Hz, 2H), 2.37 (d,J = 7.5 Hz, 1H), 2.20-1.96 (m, 5H), 1.92-1.90 (m, 1H), 1.82-1.79 (m,1H), 1.66-1.62 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H), 1.29-1.21 (m, 5H),1.19 (d, J = 10.8 Hz, 2H), 0.95-0.81 (m, 5H) J168

2-[((2S,11S)-11- amino-12-oxo-1- azatricyclo [6.4.1.0{circumflex over( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[2-chloro-3-(4-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]butyl) phenyl]pentanediamide hydrochloride 1010.35 (400 MHz, DMSO-d₆) δ 9.55 (d, J =12.7 Hz, 1H), 9.06 (s, 1H), 8.60 (dd, J = 21.6, 7.7 Hz, 1H), 8.48 (d, J= 14.4 Hz, 3H), 8.41 (d, J = 7.7 Hz, 1H), 7.88-7.81 (m, 1H), 7.59 (dd, J= 24.4, 7.9 Hz, 1H), 7.48- 7.32 (m, 4H), 7.25 (dd, J = 15.5, 7.3 Hz,1H), 7.19-6.96 (m, 4H), 6.85 (s, 1H), 5.20 (s, 1H), 4.92 (t, J = 7.2 Hz,1H), 4.52 (d, J = 9.7 Hz, 1H), 4.43 (t, J = 7.9 Hz, 2H), 4.28 (s, 1H),4.22-4.17 (m, 2H), 3.63 (d, J = 18.5 Hz, 3H), 3.54- 3.45 (m, 1H), 3.15(s, 2H), 3.01 (d, J = 16.7 Hz, 1H), 2.73-2.69 (m, 2H), 2.47 (s, 3H),2.29-2.25 (m, 3H), 2.20-2.16 (m, 1H), 2.05-2.01 (m, 2H), 1.92-1.88 (m,1H), 1.85- 1.73 (m, 1H), 1.56-1.52 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H),0.94 (s, 9H) J169

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[2-chloro-3-(3-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-[[1S)-1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]propyl) phenyl]pentanediamide hydrochloride  996.40 (400 MHz, DMSO-d₆) δ 9.49 (s, 1H),8.99 (s, 1H), 8.40 (t, J = 9.0 Hz, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.61(dd, J = 23.2, 8.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3Hz, 2H), 7.33 (s, 1H), 7.27- 7.23 (m, 1H), 7.15-7.02 (m, 4H), 7.02-6.92(m, 2H), 6.82 (s, 1H), 5.14 (dd, J = 14.8, 6.0 Hz, 2H), 4.93 (p, J = 7.2Hz, 1H), 4.55 (d, J = 9.6 Hz, 1H), 4.45 (s, 1H), 4.29 (s, 1H), 4.04 (d,J = 8.3 Hz, 1H), 3.62 (d, J = 3.1 Hz, 2H), 3.48-3.44 (m, 1H), 3.03 (s,3H), 2.68 (d, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.33- 2.29 (m, 1H),2.21-2.17 (m, 3H), 2.08-2.04 (m, 2H), 2.03-1.99 (m, 1H), 1.90-1.86 (m,1H), 1.81-1.77 (m, 2H), 1.39-1.35 (m, 5H), 1.27- 1.22 (m, 1H), 0.95 (s,9H) J170

(2S)-2-[[2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[3-(3-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]propyl) phenyl] pentanediamide hydrochloride 962.25 (400 MHz, DMSO-d₆) δ 10.14 (s, 1H), 9.11-9.06 (m, 1H), 8.57 (d,J = 7.3 Hz, 1H), 8.52 (s, 2H), 8.42 (d, J = 7.7 Hz, 1H), 8.25 (d, J =8.7 Hz, 0H), 7.87 (d, J = 9.2 Hz, 1H), 7.48-7.36 (m, 7H), 7.19 (t, J =7.7 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.98(t, J = 7.4 Hz, 1H), 6.87 (q, J = 11.5, 10.9 Hz, 2H), 5.20 (dd, J =10.9, 3.0 Hz, 1H), 4.92 (p, J = 7.0 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H),4.43 (t, J = 8.0 Hz, 1H), 4.36-4.31 (m, 1H), 4.28 (dq, J = 6.3, 3.1 Hz,1H), 4.25-4.14 (m, 2H), 3.91-3.77 (m, 1H), 3.76-3.65 (m, 1H), 3.62 (d, J= 1.6 Hz, 1H), 3.54-3.45 (m, 2H), 3.16-3.11 (m, 2H), 2.99-2.97 (m, 1H),2.47 (s, 3H), 2.28-2.25 (m, 3H), 2.21-2.12 (m, 2H), 2.09-1.86 (m, 3H),1.84-1.68 (m, 3H), 1.37- 1.33 (m, 3H), 0.94 (s, 11H) J171

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[2-chloro-3-(5-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl]pentyl) phenyl]pentanediamide hydrochloride 1024.45 (300 MHz, DMSO-d₆) δ 9.54 (d, J =10.9 Hz, 1H), 9.07 (s, 1H), 8.72- 8.36 (m, 5H), 7.81 (d, J = 9.2 Hz,1H), 7.65-7.57 (m, 1H), 7.43 (q, J = 8.2 Hz, 5H), 7.31-6.95 (m, 4H),6.86 (s, 1H), 5.23 (d, J = 10.4 Hz, 1H), 5.01-4.86 (m, 1H), 4.59-4.39(m, 3H), 4.3-4.17 (m, 2H), 3.62 (s, 2H), 3.16 (s, 2H), 3.03 (d, J = 17.0Hz, 1H), 2.74-2.68 (m, 2H), 2.48 (s, 3H), 2.38-1.71 (m, 10H), 1.63- 1.48(m, 6H), 1.39 (d, J = 6.9 Hz, 3H), 1.35-1.26 (m, 2H), 0.95 (s, 9H) J172

(2S)-2-[[2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[2-fluoro-3-(5- [[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl] pentyl)phenyl]pentanediamide hydrochloride 1008.56 (300 MHz, DMSO-d₆) δ 9.81-9.79 (m,1H), 9.09 (s, 1H), 8.60-8.48 (m, 4H), 8.41 (d, J = 7.7 Hz, 1H), 7.79 (d,J = 9.1 Hz, 1H), 7.71-7.65 (m, 1H), 7.43 (q, J = 8.2 Hz, 4H), 7.15-6.97(m, 5H), 6.85 (s, 1H), 5.26-5.16 (m, 1H), 4.93 (t, J = 7.2 Hz, 1H),4.58-4.39 (m, 3H), 4.29 (s, 1H), 4.23-4.16 (m, 1H), 3.54- 3.39 (m, 1H),3.17-3.13 (m, 2H), 3.03-2.98 (m, 1H), 2.59 (t, J = 8.4 Hz, 2H), 2.48 (s,3H), 2.35-1.70 (m, 10H), 1.61-1.47 (m, 6H), 1.39 (d, J = 7.0 Hz, 3H),1.35-1.17 (m, 3H), 0.94 (s, 9H) J173

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2-fluoro-6-methylphenyl] hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazolo- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1009.45 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s,1H), 8.51 (s, 3H), 8.41 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H),7.81 (d, J = 9.3 Hz, 1H), 7.48-7.28 (m, 4H), 7.08-6.96 (m, 3H), 6.87 (s,2H), 6.79 (s, 1H), 5.10 (dd, J = 10.9, 3.1 Hz, 1H), 4.92 (p, J = 7.2 Hz,1H), 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 7.9 Hz, 1H), 4.28 (s, 1H),4.24-4.12 (m, 1H), 4.01-3.87 (m, 2H), 3.77-3.57 (m, 3H), 3.52-3.38 (m,2H), 3.17- 3.11 (m, 3H), 2.88 (d, J = 16.9 Hz, 1H), 2.56 (s, 2H), 2.47(s, 3H), 2.33-2.24 (m, 2H), 2.21 (s, 3H), 2.19-2.08 (m, 2H), 2.07-1.97(m, 1H), 1.92-1.65 (m, 4H), 1.57-1.40 (m, 4H), 1.38 (d, J = 7.2 Hz, 3H),1.35-1.22 (m, 2H), 0.93 (s, 9H) J174

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2,6-difluorophenyl] hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1013.40 (400 MHz, DMSO-d₆) δ 9.11 (s, 1H),8.53 (s, 3H), 8.41 (d, J = 7.7 Hz, 1H), 8.32 (d, J = 7.4 Hz, 1H), 7.80(d, J = 9.3 Hz, 1H), 7.48-7.35 (m, 4H), 7.33 (s, 1H), 7.10-6.91 (m, 4H),6.80 (s, 1H), 5.10 (dd, J = 10.9, 3.1 Hz, 1H), 4.91 (q, J = 7.3 Hz, 1H),4.51 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H),4.21-4.12 (m, 1H), 4.06-3.89 (m, 4H), 3.69-3.57 (m, 3H), 3.50- 3.38 (m,1H), 3.21-3.08 (m, 2H), 2.87 (d, J = 16.4 Hz, 1H), 2.58 (d, J = 8.0 Hz,2H), 2.47 (s, 3H), 2.30- 1.98 (m, 4H), 1.94-1.68 (m, 3H), 1.60 (s, 1H),1.55-1.43 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H), 1.31-1.22 (m, 2H), 0.92 (s,9H) J175

(2S,4R))-1-[(2S)-2- (4-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- chlorophenyl]butanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  983.50 (400 MHz, DMSO-d₆) δ 9,15 (d, J = 1.5Hz, 1H), 8.57 (s, 3H), 8.43 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 7.5 Hz,1H), 7.90 (d, J = 9.3 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.40 (d, J =8.2 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 7.5 Hz, 2H), 7.00(d, J = 7.8 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H), 6.85-6.71 (m, 1H), 5.11(dd, J = 10.9, 3.1 Hz, 1H), 4.93 (p, J = 7.0 Hz, 1H), 4.55 (d, J = 9.1Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.17 (s, 1H), 4.05 (d,J = 7.5 Hz, 2H), 3.95 (s, 1H), 3.63 (d, J = 12.2 Hz, 3H), 3.49-3.37 (m,1H), 3.16-3.12 (m, 2H), 2.98-2.94 (m, 1H), 2.71-2.67 (m, 2H), 2.48 (s,3H), 2.39-2.24 (m, 2H), 2.24- 2.12 (m, 3H), 2.10-1.98 (m, 2H), 1.93-1.85(m, 1H), 1.83-1.68 (m, 4H), 1.38 (d, J = 7.0 Hz, 3H), 0.95 (s, 9H) J176

4-[3-[(2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-4-carbamoylbutyl)- (methyl)amino]-2- fluorophenyl]butylN-[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamate hydrochloride 1010.45 (400 MHz, DMSO-d₆) δ 9.08(s, 1H), 8.50 (s, 2H), 8.43 (d, J = 7.7 Hz, 1H), 8.03 (dd, J = 16.6, 8.6Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.25 (s,1H), 7.08-6.95 (m, 3H), 6.97-6.88 (m, 2H), 6.79 (s, 3H), 5.01-4.86 (m,1H), 4.45 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.17 (d, J = 9.2 Hz, 2H),4.01 (s, 1H), 3.95 (s, 2H), 3.57 (s, 2H), 3.53-3.37 (m, 1H), 3.32-3.15(m, 1H), 2.76 (s, 2H), 2.59-2.56 (m, 3H), 2.47 (s, 3H), 2.26-2.21 (m,3H), 2.07-2.03 (m, 4H), 1.80- 1.76 (m, 1H), 1.62-1.58 (m, 6H), 1.52-1.48(m, 1H), 1.43-1.35 (m, 3H), 1.29-1.25 (m, 2H), 1.18-1.07 (m, 1H), 0.94(s, 9H) J177

(2S,4R)-1-[(2S)-2- (2-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- phenyl]acetamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride [(M − 1)]⁻ = 919.50 (300 MHz, DMSO-d₆) δ 9.15(s, 1H), 8.57-8.29 (m, 4H), 8.06 (d, J = 9.2 Hz, 1H), 7.53-7.38 (m, 4H),7.25-6.67 (m, 8H), 5.20-4.81 (m, 2H), 4.62-4.37 (m, 2H), 4.32-3.83 (m,5H), 3.63 (d, J = 13.8 Hz, 2H), 3.42 (dd, J = 13.6, 6.2 Hz, 2H), 3.15(s, 2H), 2.87 (d, J = 16.8 Hz, 1H), 2.49 (s, 3H), 2.36-1.65 (m, 9H),1.38 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H) J178

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[3-chloro-5-(5-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-[[(1S)-l-[4-(4-methyl-1,3-thiazol- 3- yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl] pentyl)phenyl]pentanediamide hydrochloride [(M − 1)]⁻ = 1022.65 (300 MHz, DMSO-d₆) δ10.44 (s, 1H), 9.12 (s, 1H), 8.63 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 7.7Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.67 (s, 1H), 7.50-7.39 (m, 6H), 7.32(s, 1H), 7.19-6.93 (m, 6H), 5.21 (d, J = 10.7 Hz, 1H), 4.99-4.88 (m,1H), 4.52 (d, J = 9.1 Hz, 1H), 4.44 (t, J = 8.1 Hz, 1H), 4.32 (d, J =13.3 Hz, 2H), 4.30-4.20 (s, 1H), 3.51-3.33 (m, 2H), 3.06-2.94 (m, 1H),2.48 (s, 3H), 2.33-1.88 (m, 11H), 1.43- 1.19 (m, 9H), 1.17-0.98 (m, 2H),0.94 (s, 9H) J179

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[3-(5-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl)- 5- methylphenyl] pentanediamidehydrochioride 1004.45 (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 8.99 (s, 1H),8.57-8.43 (m, 3H), 7.80 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H),7.38 (d, J = 8.2 Hz, 2H), 7.36-7.30 (m, 1H), 7.26- 7.21 (m, 2H), 7.10(d, J = 7.5 Hz, 2H), 7.04 (d, J = 7.9 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H),6.79 (s, 1H), 6.70 (s, 1H), 5.18-5.03 (m, 2H), 4.92 (p, J = 7.2 Hz, 1H),4.52 (d, J = 9.3 Hz, 1H), 4.33-4.24 (m, 2H), 4.11-4.02 (m, 2H), 3.61 (d,J = 3.6 Hz, 2H), 3.53-3.40 (m, 2H), 3.15- 2.93 (m, 3H), 2.52-2.43 (m,5H), 2.49-2.41 (m, 2H), 2.32-2.24 (m, 2H), 2.23 (s, 3H), 2.19-1.74 (m,6H), 1.60-1.45 (m, 4H), 1.29-1.23 (m, 4H), 0.93 (s, 9H) J180

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[3-(5-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]pentyl)- 2- methylphenyl] pentanediamidehydrochioride [(M − H)]⁻ = 1002.65 (300 MHz, DMSO-d₆) δ 9.51 (d, J = 4.1Hz, 1H), 9.44-9.19 (m, 1H), 8.63-8.60 (m, 5H), 8.42 (d, J = 7.8 Hz, 1H),7.78 (d, J = 9.1 Hz, 1H), 7.42 (q, J = 8.1 Hz, 4H), 7.24-6.92 (m, 8H),5.20 (dd, J = 10.9, 3.1 Hz, 1H), 4.96-4.90 (m, 1H), 4.56-4.35 (m, 3H),4.27 (s, 1H), 4.16 (d, J = 8.1 Hz, 1H), 3.70-3.57 (m, 3H), 3.51-3.28 (m,1H), 3.12 (s, 2H), 2.99 (d, J = 16.8 Hz, 1H), 2.55 (d, J = 7.9 Hz, 2H),2.46 (s, 3H), 2.37- 2.16 (m, 2H), 2.17-2.07 (m, 3H), 2.02-1.84 (m, 4H),1.85-1.63 (m, 1H), 1.63-1.40 (m, 5H), 1.36 (d, J = 6.9 Hz, 3H), 1.27(dd, J = 17.8, 10.3 Hz, 1H), 1.10-1.05 (m, 1H), 0.92 (s, 9H) J181

(2S,4R)-1-[(2S)-2- (3-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]-phenyl]propanamido)- 3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  935.12 (400 MHz, DMSO-d₆) δ 9.10 (s, 1H),8.57 (s, 6H), 8.43 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.89(d, J = 9.3 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H),7.17 (t, J = 7.6 Hz, 2H), 7.13- 6.98 (m, 4H), 6.80 (d, J =8.1 Hz, 1H),6.73 (d, J = 7.9 Hz, 1H), 5.10 (dt, J = 11.3, 3.6 Hz, 2H), 4.92 (p, J =7.0 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz, 1H), 4.29(s, 1H), 4.20 (dq, J = 11.8, 6.5 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.90(t, J = 5.7 Hz, 1H), 3.61-3.58 (m, 2H), 3.51-3.37 (m, 1H), 3.15- 3.10(m, 3H), 2.90-2.70 (m, 3H), 2.60-2.55 (m, 1H), 2.47 (s, 3H), 2.35-2.02(m, 4H), 1.79-1.75 (m, 1H), 1.37-1.34 (m, 4H), 0.90 (s, 9H) J182

(2S,4R)-1-[(2S)- (4-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl)formamido]-4- carbamoylbutoxy]- 2- fluorophenyl]butanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-|(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  967.35 (400 MHz, DMSO-d₆) δ 9.06 (s, 1H),8.53-8.49 (m, 2H), 8.41 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H),7.89 (d, J = 9.2 Hz, 1H), 7.48- 7.42 (m, 2H), 7.43-7.39 (m, 2H),7.32-7.30 (m, 1H), 7.11-7.05 (m, 2H), 7.03-6.97 (m, 3H), 6.87-6.76 (m,2H), 5.10 (dd, J = 11.0, 3.1 Hz, 1H), 4.91 (q, J = 7.3 Hz, 1H), 4.54 (d,J = 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.29-4.27 (m, 1H), 4.24- 4.13(m, 1H), 4.02 (m, 2H), 3.61 (t, J = 3.2 Hz, 2H), 3.46-3.36 (m, 2H),3.16-3.13 (m, 1H), 2.90-2.83 (m, 1H), 2.59 (t, J = 8.0 Hz, 2H), 2.47 (s,3H), 2.34-2.28 (m, 1H), 2.25-2.18 (m, 3H), 2.13-2.05 (m, 2H), 2.03-1.98(m, 2H), 1.86-1.69 (m, 6H), 1.38 (d, J = 7.1 Hz, 3H), 0.94 (s, 9H) J183

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2-fluoro-5- methylphenyl] hexanamido)-3,3-dimethylbutanoyl]- 4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride 1032.45 (300MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.63-8.45 (m, 3H), 8.38 (d, J = 8.0 Hz,2H), 8.22-8.15 (m, 1H), 7.82-7.73 (m, 1H), 7.41 (q, J = 8.2 Hz, 4H),6.80 (d, J = 7.7 Hz, 1H), 6.60 (d, J = 5.9 Hz, 1H), 4.91 (t, J = 7.2 Hz,1H), 4.54-4.35 (m, 4H), 4.30-4.19 (m, 3H), 4.09-3.94 (m, 3H), 3.91-3.82(m, 2H), 3.81-3.68 (m, 2H), 3.60 (s, 3 H), 3.53-3.36 (m, 2H), 3.35-3.08(m, 3H), 2.46 (s, 3H), 2.22 (s, 3H), 1.99 (d, J = 9.9 Hz, 2H), 1.87-1.78(m, 4H), 1.77-1.66 (m, 4H), 1.59-1.42 (m, 6H), 1.36 (s, 3H), 1.30-1.20(m, 3H), 0.92 (s, 9H) J184

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl)formamido]-4-carbamoylbutoxy]- 2- fluorophenyl] pentanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride 1004.40 ¹H NMR (400 MHz,DMSO-d₆) δ 9.03 (s, 1H), 8.49-8.47 (m, 1H), 8.40 (d, J = 7.8 Hz, 1H),8.34 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 9.3 Hz, 1H), 7.45(d, J = 8.3 Hz, 2H), 7.39 (d, J = 8 3 Hz, 2H), 7.25 (s, 1H), 7.02-7.00(m, 2H), 6.82 (t, J = 6.4 Hz, 1H), 6.77 (s, 1H), 4.93 (t, J = 7.0 Hz,1H), 4.50 (d, J = 12.5 Hz, 2H), 4.42-4.38 (m, 2H), 4.32-4.21 (m, 3H),4.02 (d, J = 9.5 Hz, 2H), 3.92 (t, J = 9.8 Hz, 1H), 3.81-3.73 (m, 1H),3.63-3.58 (m, 2H), 3.29-3.12 (m, 1H), 2.59 (t, J = 7.8 Hz, 2H), 2.47 (s,3H), 2.35-2.28 (m, 1H), 2.22-2.15 (m, 3H), 2.12 (d, J = 9.9 Hz, 4H),2.06- 1.91 (m, 3H), 1.90-1.75 (m, 5H), 1.72-1.69 (m, 2H), 1.52-1.45 (m,5H), 1.38 (d, J = 7.1 Hz, 3H), 0.93 (s, 9H) J185

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-[3-fluoro-5-(5-[[(2S)-1- [(2S,4R)-4-hydroxy- 2-[[(1S)-1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] carbamoyl] pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl] pentyl)phenyl]-pentanediamide hydrochloride [(M − H)]⁻ = 1006.60 (300 MHz, DMSO-d₆) δ10.53 (d, J = 20.0 Hz, 1H), 9.41 (d, J = 10.0 Hz, 1H), 8.67 (d, J = 13.7Hz, 5H), 8.48 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.52-7.39(m, 6H), 7.23 (s, 1H), 7.18-6.91 (m, 3H), 6.77-6.65 (m, 1H), 5.23 (dd, J= 11.1, 2.9 Hz, 1H), 4.94 (t, J = 7.2 Hz, 1H), 4.59-4.40 (m, 3H), 4.43-4.24 (m, 2H), 4.18 (d, J = 9.4 Hz, 1H), 3.65 (d, J = 17.5 Hz, 2H),3.52-3.26 (m, 2H), 3.14 (s, 2H), 3.00 (d, J = 16.9 Hz, 1H), 2.40- 1.70(m, 8H), 1.67-1.43 (m, 8H), 1.39 (d, J = 6.9 Hz, 3H), 1.33-1.18 (m, 2H),1.18-1.00 (m, 1H), 0.94 (s, 9H) J186

(2S,4R)-1-[(2S)-2- (6-[3-[(2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca- 4(13),5,7-trien-2-yl]formamido]-4- carbamoylbutyl) amino]-2- fluorophenyl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide trifluoroacetate  994.45 (400 MHz, DMSO-d₆) δ 9.01 (s, 1H),8.36 (s, 3H), 8.12 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.44(d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.22 (s, 1H), 7.11- 7.02(m, 3H), 7.04-6.96 (m, 1H), 6.83 (t, J = 8.0 Hz, 1H), 6.77 (s, 1H), 6.63(t, J = 8.3 Hz, 1H), 6.41 (t, J = 7.0 Hz, 1H), 5.04 (dd, J = 10.8, 3.2Hz, 1H), 4.91 (p, J = 7.3 Hz, 1H), 4.55-4.49 (m, 2H), 4.47- 4.38 (m,2H), 4.28 (s, 1H), 3.84 (s, 1H), 3.64-3.58 (m, 3H), 3.42 (dd, J = 17.1,11.0 Hz, 1H), 3.14-3.07 (m, 2H), 2.85-2.81 (m, 1H), 2.49- 2.44 (m, 6H),2.32-2.20 (m, 1H), 2.19-2.07 (m, 2H), 2.11-2.07 (m, 2H), 1.83-1.79 (m,1H), 1.56-1.52 (m, 4H), 1.41-1.35 (m, 6H), 1.32- 1.22 (m, 3H), 0.94 (s,9H) J187

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2-fluoro-5-methylphenyl] hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1009.50 (300 MHz, DMSO-d₆) δ 9.06 (s, 1H),8.61-8.45 (m, 3H), 8.38 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 7.4 Hz, 1H),7.78 (d, J = 9.2 Hz, 1H), 7.41 (q, J = 8.3 Hz, 4H), 7.10-6.94 (m, 3H),6.83-6.74 (m, 2H), 6.61 (d, J = 5.9 Hz, 1H), 5.09 (dd, J = 10.9, 3.0 Hz,1H), 4.96-4.83 (m, 1H), 4.50 (d, J = 9.3 Hz, 1H), 4.42 (t, J = 8.0 Hz,1H), 4.30-4.23 (m, 1H), 4.21-4.11 (m, 1H), 4.03-3.89 (m, 3H), 3.61-3.58(m, 2H), 3.56 (s, 3H), 3.49-3.34 (m, 1H), 3.18-3.07 (m, 2H), 2.86 (d, J= 16.5 Hz, 1H), 2.45 (s, 3H), 2.32-2.23 (m, 2H), 2.17-1.95 (m, 5H), 188-1.70 (m, 4H), 1.62-1.42 (m, 5H), 1.36 (s, 3H), 1.35-1.20 (m, 3H),0.92 (s, 9H) J188

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2,5-difluorophenyl] hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride 1013.35 (400 MHz, CD3OD) δ 9.99 (s, 1H),7.61-7.45 (m, 4H), 7.12 (d, J = 7.5 Hz, 2H), 7.10-7.01 (m, 1H),6.83-6.75 (m, 1H), 6.64-6.55 (m, 1H), 5.20 (dd, J = 11.0, 3.5 Hz, 1H),5.03 (q, J = 7.0 Hz, 1H), 4.65- 4.55 (m, 2H), 4.44 (br, 1H), 4.30- 4.09(m, 2H), 4.07-3.98 (m, 1H), 3.90 (d, J = 11.1 Hz, 1H), 3.76 (dd, J =11.1, 4.1 Hz, 1H), 3.64-3.49 (m, 1H), 3.27 (s, 2H), 3.10 (dd, J = 16.9,3.6 Hz, 1H), 2.68-2.58 (m, 2H), 2.63 (s, 3H), 2.47-2.17 (m, 5H),2.10-1.87 (m, 2H), 1.71-1.55 (m, 4H), 1.53 (d, J = 7.0 Hz, 3H),1.43-1.27 (m, 4H), 1.05 (s, 9H), 0.92-0.87 (m, 2H) J189

(2S,4R)-1-[(2S)-2- (6-[2-[(1S)-1- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-3- carbamoylpropyl] pyridin-4-yl]hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  948.40 (300 MHz, DMSO-d₆) δ 9.36-9.34 (d, J =6.9 Hz, 1H), 9.08 (s, 1H), 8.73-8.71 (d, J = 6.1 Hz, 1H), 8.62-8.55 (m,3H), 8.42-8.40 (d, J = 7.7 Hz, 1H), 7.91-7.85 (m, 1H), 7.85-7.76 (m,2H), 7.50-7.33 (m, 3H), 7.08-7.02 (m, 2H), 7.00-6.90 (m, 1H), 6.83 (s,1H), 5.23-5.18 (dd, J = 11.0, 3.2 Hz, 1H), 4.93- 4.83 (m, 2H), 4.52-4.45(m, 1H), 4.44-4.42 (m, 1H), 4.27 (s, 1H), 3.54-3.29 (m, 3H), 3.11 (s,3H), 3.03-2.98 (m, 2H), 2.96-2.81 (m, 2H), 2.78 (s, 1H), 2.54-2.41 (m,6H), 2.31-2.14 (m, 2H), 2.05-1.90 (m, 1H), 1.95 (s, 1H), 1.85-1.65 (m,1H), 1.53 (s, 2H), 1.38-1.23 (m, 5H), 1.10-1.06 (t, J = 7.0 Hz, 4H),0.92 (s, 9H) J190

(2S)-2-[[(2S,11S)-- 11-amino-7-([6-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]hexyl]oxy)-12- oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-N- (diphenylmethyl) pentanediamidetrifluoroacetate  897.40 (300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.81 (d, J= 8.5 Hz, 1H), 8.46- 8.38 (m, 4H), 7.37-7.28 (m, 11H), 7.11-6.98 (m,3H), 6.97-6.82-6.78 (m, 1H), 6.71-6.67 (m 1H), 6.12 (d, J = 8.3 Hz, 1H),5.42-5.30 (m, 1H), 5.10 (dd, J = 11.2, 4.1 Hz, 1H), 4.35 (d, J = 7.0 Hz,1H), 4.20 (d, J = 10.5 Hz, 1H), 4.04-3.90 (m, 4H), 3.34 (s, 3H),3.27-3.19 (m, 2H), 2.99-2.57 (m, 6H), 2.30-2.08 (m, 2H), 2.08-1.87 (m,2H), 1.74- 1.67 (m, 4H), 1.57-1.34 (m, 4H), 1.28-1.22 (m, 2H) J191

(2S)-2-[[(2S,11S)- 11-amino-7-[4-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]butoxy]-12-oxo- 1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-N- (diphenylmethyl) pentanediamidetrifluoroacetate  869.35 (300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.83 (t, J= 10.4 Hz, 1H), 8.41-8.34 (m, 3H), 7.36-7.26 (m, 11H), 7.11-6.97 (m,3H), 6.95- 6.75 (m, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.18-6.02 (m, 1H),5.36 (dd, J = 12.9. 5.1 Hz, 1H), 5.28-5.05 (m, 1H), 4.45-4.09 (m, 2H),4.06- 3.98 (m, 2H), 3.35 (s, 3H), 3.31- 3.00 (m, 2H), 3.00-2.57 (m, 6H),2.09-1.96 (m, 6H), 1.86-1 78 (m, 6H) J192

(5S,8S,10aR)-8- [[(1S)-3-carbamoyl- 1- (diphenylmethyl-carbamoyl)propyl] carbamoyl]-6-oxo- 3-[4- ((1r,4s)-4-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]cyclohexyl]butanoyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-5- aminidetrifluoroacetate  930.65 (400 MHz, CDCl₃) δ 9.88 (s, 1H), 8.43-8.34 (m,1H), 7.89-7.78 (m, 1H), 7.28-7.16 (m, 9H), 6.93-6.84 (m, 2H), 6.74-6.72(m, 1H), 6.12 (d, J = 7.9 Hz, 1H), 6.01-5.98 (m, 1H) 5.17-5.14 (m, 1H),4.44-3.93 (m, 10H), 3.20 (m, 8H), 3.01-1.87 (m, 22H), 1.77-1.71 (m, 4H),1.41 (d, J = 8.4 Hz, 2H), 1.21 (d, J = 2.8 Hz, 1H), 1.17 (d, J = 3.1 Hz,1H), 1.17-1.15 (m, 2H), 1.15-1.13 (m, 1H) J193

(3R,5S)-1-[(2S)-2- (6-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- fluorophenyl]hexanamido)-3,3- dimethylbutanoyl]- 5-[[(1S)-1-[4-(4-methyl-1,3-thiazol- 5- yl)phenyl]ethyl] carbamoyl] pyrrolidin-3- ylacetate hydrochloride 1037.40 (400 MHz, DMSO-d₆) δ 9.08 (s, 1H),8.58-8.43 (m, 4H), 8.31 (d, J = 7.3 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H),7.49-7.36 (m, 4H), 7.39-7.29 (m, 1H), 7.10-7.03 (m, 2H), 7.03- 6.95 (m,3H), 6.83 (s, 1H), 5.18 (s, 1H), 5.10 (dd, J = 10.9, 3.1 Hz, 1H), 4.92(p, J = 7.2 Hz, 1H), 4.47 (t, J = 8.3 Hz, 1H), 4.35 (d, J = 8.8 Hz, 1H),4.24-4.14 (m, 1H), 4.02 (d, J = 7.2 Hz, 1H), 3.99-3.91 (m, 2H),3.79-3.57 (m, 2H), 3.52-3.37 (m, 1H), 3.14 (d, J = 6.9 Hz, 2H),2.90-2.86 (m, 1H), 2.59-2.56 (m, 3H), 2.47 (s, 3H), 2.30-2.18 (m, 3H),2.19-2.04 (m, 1H), 1.99 (s, 3H), 1.91-1.82 (m, 1H), 1.80-1.69 (m, 2H),1.60 (s, 1H), 1.53-1 49 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H), 1.29-1.25 (m,2H), 0.95 (s, 9H) J194

(2S)-2- [[(5S,8S,10aR)-5-- amino-6-oxo-3-[3- [(1s,4s)-4-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]cyclohexyl]propanoyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-N-(diphenylmethyl) pentanediamide trifluoroacetate [(M − 1)]⁻ = 914.15(300 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.85 (t, J = 7.7 Hz, 1H), 8.32 (d, J= 11.4 Hz, 3H), 7.40-7.21 (m, 10H), 7.11-6.98 (m, 2H), 6.91 (d, J = 8.3Hz, 1H), 6.79 (s, 1H), 6.12 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 5.35 (dd,J = 12.5, 5.2 Hz, 1H), 4,53-4.39 (m, 3H), 4.24 (s, 1H), 4.02 (d, J =13.9 Hz, 1H), 3.84- 3.49 (m, 2H), 3.30-3.16 (m, 1H), 2.96-2.91 (m, 1H),2.76-2.58 (m, 1H), 2.16 -2.11(m, 4H), 2.07-1.66 (m, 14H), 1.58-1.41 (m,4H), 1.35- 1.32 (m, 3H), 1.25-1.21 (m, 2H), 1.10-1.05 (m, 2H) J195

(5S,8S,10aR)-8- [[(1S)-3-carbamoyl- 1- (diphenylmethyl-carbamoyl)propyl] carbamoyl]-6-oxo- 3-[4- [(1s,4r)-4-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]cyclohexyl]butanoyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-5- aminidetrifluoroacetate  930.50 (400 MHz, CDCl3) δ 11.32-11.20 (m, 10H),11.00-10.98 (m, 1H), 10.96-10.90 (m, 2H), 10.11 (s, 1H), 9.29-9.26 (m,1H), 8.51-8.43 (m, 2H), 8.29-8.25 (m, 1H), 8.16 (s, 1H), 7.84 (d, J =15.9 Hz, 1H), 7.66-7.63 (m, 1H), 7.39-7.35 (m, 3H), 6.93-6.82 (m, 1H),6.75 (d, J = 15.5 Hz, 2H), 6.55-6.52 (m, 2H), 6.39-6.32 (m, 4H),6.15-6.04 (m, 3H), 5.92-5.87 (m, 6H), 5.68 (s, 2H), 5.52-5.49 (m, 2H),5.32-5.28 (m, 3H), 5.16-5.12 (m, 8H) J196

(2S,4R)-1-[(2S)-2- (6-(3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2- fluorophenyl] hexanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride 1018.45 (400 MHz, DMSO-d₆) δ9.09 (s, 1H), 8.54 (s, 1H), 8.44-8.35 (m, 2H), 8.21 (d, J = 7.8 Hz, 1H),7.80 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz,2H), 7.38-7.17 (m, 2H), 7.00 (s, 2H), 6.84-6.80 (m, 1H), 4.93-4.89 (m,1H), 4.55-4.33 (m, 4H), 4.26 (d, J = 16.4 Hz, 3H), 4.03 (t, J = 14.0 Hz,3H), 3.92 (t, J = 8.0 Hz, 1H), 3.77 (d, J = 14.3 Hz, 1H), 3.71- 3.58 (m,2H), 3.48-3.44 (m, 1H), 3.24-3.18 (m, 1H), 2.56 (t, J = 7.6 Hz, 3H),2.47 (s, 3H), 2.32-2.23 (m, 1H), 2.23-2.08 (m, 6H), 2.07- 1.61 (m, 6H),1.60-1.42 (m, 7H), 1.38 (d, J = 7.0 Hz, 3H), 1.31-1.22 (m, 2H), 0.93 (s,9H) J197

(2S,4R)-1-[(2S)-2- (5-[3-[(2S)-2-[[(2S)- 1-[(S)-2-amino-4-methylpentanoyl] pyrrolidin-2- yl]formamido]-4- carbamoylbutoxy]- 2-fluorophenyl] hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]ethyl] pyrrolidine-2-carboxamide hydrochloride  963.45 (400 MHz, DMSO-d₆) δ 9.06 (s, 1H),8.40 (d, J = 7.8 Hz, 1H), 8.21 (s, 2H), 8.04 (d, J = 8.1 Hz, 1H), 7.82(d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.42-7.36 (m, 2H), 7.28(s, 1H), 7.16 (s, 1H), 7.00 (t, J = 6.7 Hz, 2H), 6.81 (d, J = 7.8 Hz,1H), 4.92 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.47-4.34 (m,1H), 4.27 (t, J = 7.0 Hz, 1H), 4.10 (s, 1H), 3.98-3.94 (m, 1H), 3.73 (s,1H), 3.69-3.59 (m, 6H), 3.47-3.37 (m, 1H), 2.59-2.56 (m, 3H), 2.47 (s,3H), 2.34-2.26 (m, 1H), 2.16 (s, 3H), 2.08 (s, 1H), 2.03-1.94 (m, 1H),1.90-1.80 (m, 1H), 1.80-1.73 (m, 5H), 1.60 (s, 1H), 1.57-1.53 (m, 5H),1.38 (d, J = 7.0 Hz, 3H), 0.94 (s, 15H) J198

(4S)-4-[[(2S,11S)- 11-amino-6-[6-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]hexyl]-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- (pyridin-2- yl)butanamidetrifluoroacetate  749.30 (300 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.75-8.68(m, 1H), 8.59-8.54 (m, 1H), 8.40-8.29 (m, 2H), 7.90- 7.83 (m, 1H),7.42-7.33 (m, 2H), 7.20 (s, 1H), 7.03-6.94 (m, 2H), 6.89 (s, 1H),6.87-6.81 (m, 2H), 6.78-6.70 (m, 1H), 5.34-5.30 (m, 1H), 5.18-5.13 (m,1H), 4.84-4.75 (m, 1H), 4.24-4.12 (m, 1H), 3.48- 3.34 (m, 2H), 3.14-3.03(m, 2H), 2.92-2.69 (m, 3H), 2.68-2.54 (m, 4H), 2.46-2.37 (m, 2H),2.19-1.92 (m, 8H), 1.60-1.44 (m, 4H), 1.35- 1.25 (m, 4H) J199

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[3- [(1r,4r)-4-[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]cyclohexyl]propanoyl]- octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido]-N-(diphenylmethyl) pentanediamide trifluoroacetate  916.40 (300 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.85 (t, J = 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz,2H), 7.41-7.19 (m, 12H), 7.09 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.93(d, J = 8.1 Hz, 1H), 6.79 (s, 1H), 6.12 (d, J = 8.1 Hz, 1H), 5.35 (dd, J= 12.8. 5.3 Hz, 1H), 4.58-4.33 (m, 4H), 4.24-4.21 (m, 1H), 4.02 (d, J =14.3 Hz, 1H), 3.86-3.84 (m, 2H), 3.09-2.84 (m, 3H), 2.64-2.61 (m, 2H),2.10-2.07 (m, 11H), 1.87-1.53 (m, 14H) J200

(2S,4R)-1-[(2S)-2- (6-[3-[(2S)-2-[[(2S)- 1-[(2S)-2-amino-4-methylpentanoyl] pyrrolidin-2- yl]formamido]-4- carbamoylbutoxy]- 2-fluorophenyl] hexanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl)ethyl] pyrrolidine-2-carboxamide hydrochloride  977.45 (400 MHz, DMSO-d₆) δ 9.02 (d, J = 1.8Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.17-8.15 (m, 2H), 8.02 (d, J = 8.0Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d, J= 8.2 Hz, 2H), 7.00 (d, J = 6.9 Hz, 2H), 6.84-6.75 (m, 1H), 4.93- 4.91(m, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.43-4.41 (m, 2H), 4.38-4.30 (m, 4H),4.06-3.87 (m, 4H), 3.73 (d, J = 8.9 Hz, 2H), 3.51-3.38 (m, 2H),2.58-2.55 (m, 3H), 2.46 (s, 3H), 2.31-2.21 (m, 2H), 2.18-1.92 (m, 7H),1.85-1.80 (m, 7H), 1.59- 1.45 (m, 7H), 1.39-1.36 (m, 3H), 1.29-1.24 (m,2H), 0.93 (s, 9H) J201

(2S)-2-[[(2S,11S)- 11-amino-12-oxo-1- azatricyclo [6.4.1.0{circumflexover ( )}[4,13]] trideca- 4(13),5,7-trien-2- yl]formamido]-N-(3-(4-[[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl) phenyl] pentanediamide hydrochloride [(M− H)]⁻ = 974.10 Used next step directly without purification J202

4-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca- 4(13),5,7-trien-2-yl]formamido]-4- carbamoylbutoxy]- 2-fluorophenyl]butylN-[(2S)-1-[(2S,4R)- 4-hydroxy-2-[[(1S)- 1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2- yl]carbamate hydrochloride  997.75 ¹H NMR (400 MHz, DMSO-d₆)δ 9.03 (s, 1H), 8.52-8.41 (m, 2H), 8.30(d, J = 7.2 Hz, 1H), 7.47-7.42(m, 2H), 7.39 (d, J = 12.3 Hz, 2H), 7.29 (d, J = 10.2 Hz, 2H), 7.15 (s,2H), 7.07 (d, J = 7.3 Hz, 2H), 7.04- 6.96 (m, 2H), 6.92 (d, J = 9.1 Hz,1H), 6.85 (q, J = 5.1, 4.3 Hz, 1H), 5.10 (dd, J = 10.9, 3.1 Hz, 1H),4.90 (t, J = 7.2 Hz, 1H), 4.46 (dd, J = 18.7, 10.8 Hz, 2H), 4.28 (s,1H), 4.17 (d, J = 9.2 Hz, 2H), 4.01 (s, 3H), 3.63 (dt, J = 16.4. 6.5 Hz,1H), 3.50-3.37 (m, 1H), 3.15 (s, 2H), 2.88 (d, J = 16.4 Hz, 1H), 2.62(s, 2H), 2.46 (s, 3H), 2.28- 2.11 (m, 1H), 2.08 (s, 4H), 2.03 (s, 1H),1.78 (dq, J = 9.8, 3.4 Hz, 2H), 1.64-1.52 (m, 6H), 1.38 (d, J = 7.1 Hz,3H), 1.29-1.18 (m, 1H), 0.94 (s, 9H) J203

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3-[2- [(1s,4s)-4-[[1-(2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]methyl]-cyclohexyl]acetyl]- octahydropyrrolo[1, 2- a][1,5]diazocin-8-yl]formamido]-N- [[4-(propane-2- sulfonyl)phenyl] methyl] pentanediamidetrifluoroacetate  946.20 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.63-8.48(m, 1H),8.24 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.53 (dd, J= 8.2, 6.5 Hz, 2H), 7.26 (s, 1H), 7.15- 6.94 (m, 2H), 6.93-6.67 (m, 2H),5.34 (dd, J= 12.7, 5.4 Hz, 1H), 4.46-4.35 (m, 3H), 4.27- 3.88 (m, 2H),3.80-3.58 (m, 2H), 3.50-3.38 (m, 2H), 3.32- 3.18 (m, 5H), 3.01-2.84 (m,2H), 2.76-2.68 (m, 1H), 2.65- 2.59 (m, 3H), 2.38-2.25 (m, 1H), 2.18-2.12(m, 4H), 2.07- 1.52 (m, 9H), 1.52-1.19 (m, 10H), 1.14 (dd, J = 6.9, 2.8Hz, 6H) J204

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(2S,11S)-11- amino-12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4,13]] trideca-4(13),5,7-trien-2- yl]formamido]-4- carbamoylbutoxy]- 2- chlorophenyl]butanamido)-3,3- dimethylbutanoyl]- 4-hydroxy-N-[1- [4-(4-methyl-1,3-thiazol-5- yl)phenyl] cyclopropyl] pyrrolidine-2- carboxamidehydrochloride  995.45 (300 MHz, DMSO-d₆) δ 9.09- 9.02 (m, 1H), 8.88-8.82(m, 1H), 8.53-8.47 (m, 2H), 8.30 (d, J = 12 Hz, 1H), 8.04 (d, J = 9.3Hz, 1H), 7.38-7.28 (m, 5H), 7.26-7.18 (m, 1H), 7.14-7.03 (m, 2H),7.10-7.01 (m, 2H), 6.96-6.91 (m, 1H), 6.87-6.80 (m, 1H), 5.16-5.10 (m,1H), 4.62-4.56 (m, 1H), 4.14-4.01 (m, 4H), 3.69-3.64 (m, 2H), 3.49-3.38(m, 1H), 3.18-3.12 (m, 2H), 3.02-2.93 (m, 1H), 2.73-2.65 (m, 2H), 2.46(s, 3H), 2.40-2.31 (m, 1H), 2.29-1.97 (m, 8H), 1.93-1.69 (m, 6H),1.27-1.15 (m, 4H), 0.97 (s, 9H) J205

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2- a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2- chlorophenyl] butanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-[1- [4-(4-methyl-1,3- thiazol-5- yl)phenyl] cyclopropyl]pyrrolidine-2- carboxamide hydrochloride 1018.50 (300 MHz, DMSO-d₆) δ9.07 (s, 1H), 8.89-8.81 (m, 1H), 8.55-8.49 (m, 1H), 8.42-8.35 (m, 1H),8.20 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.37-7.28 (m, 5H),7.27-7.20 (m, 1H), 7.05-7.00 (m, 1H), 6.95-6.89 (m, 1H), 6.78 (s, 1H),4.58 (d, J = 9.3 Hz, 1H), 4.44- 4.35 (m, 3H), 4.29-4.23 (m, 2H),4.09-4.02 (m, 2H), 3.97- 3.93 (m, 1H), 3.69-3.62 (m, 2H), 3.62-3.56 (m,4H), 3.09- 3.01 (m, 1H), 2.72-2.64 (m, 2H), 2.46 (s,3H), 2.26-2.10 (m,8H), 2.05-1.98 (m, 2H), 1.93- 1.73 (m, 10H), 1.26-1.14 (m, 4H), 0.96 (s,9H) J206

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3- [(1r,4r)-4-[2-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]ethyl]cyclohexanecarbonyl]- octahydropyrrolo[1, 2- a][1,5]diazocin-8-yl]formamido]-N- [(4- methane- sulfonylphenyl) methyl] pentanediamidetrifluoroacetate  918.35 (300 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.62 (d, J= 6.2 Hz, 1H), 8.46-8.26 (m, 3H), 7.88 (d, J = 7.8 Hz, 2H), 7.56-7.48(m, 2H), 7.26 (s, 1H), 7.02 (d, J = 9.6 Hz, 2H), 6.91-6.78 (m, 2H), 5.77(d, J = 1.2 Hz, 1H), 5.35 (d, J = 11.9 Hz, 1H), 4.73-4.65 (m, 16H),4.52-4.36 (m, 3H), 4.25 (dd, J = 19.0, 11.7 Hz, 1H), 3.21 (s, 3H),2.98-2.71 (m, 2H), 2.66 (s, 3H), 2.14-2.11 (m, 1H), 2.06-1.67 (m, 8H),1.52-1.47 (m, 2H), 1.37-1.01 (m, 4H) J207

(2S)-2- ((5S,8S,10aR)-5- amino-3-(2-((1r,4S)- 4-((1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5- yl)methyl)- cyclohexyl)acetyl)-6- oxodeca-hydropyrrolo[1,2- a][1,5|diazocine-8- carboxamido)-N- (4-(methylsulfonyl) benzyl) pentanediamide trifluoroacetate  918.40 (300MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.57 (q, J = 4.0, 2.5 Hz, 1H), 8.36 (d, J= 7.7 Hz, 1H), 8.27 (s, 2H), 7.90-7.80 (m, 2H), 7.49 (d, J = 8.3 Hz,2H), 7.25- 7.19 (m, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.87-6.74 (m, 2H),5.33 (dd, J = 12.8, 5.3 Hz, 1H), 4.51-4.34 (m, 4H), 4.30-4.09 (m, 3H),3.99-3.88 (m, 1H), 3.81 (d, J = 14.4 Hz, 1H), 3.31 (s, 3H), 3.18 (s,3H), 3.14-2.81 (m, 3H), 2.77-2.55 (m, 3H), 2.38-2.07 (m, 6H), 2.04-1.62(m, 13H), 1.04-0.86 (m, 4H) J208

(2S)-2- ((5S,8S,10aR)-5- amino-3-(7-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-5- yl)heptanoyl)-6-oxodecahydro- pyrrolo[1,2- a][1,5]diazocine-8- carboxamido)-N1- (4-(methylsulfonyl) benzyl) pentanediamide trifluoroacetate  892.40 (400MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.62-8.56 (m, 1H), 8.39 (d, J = 7.7 Hz,1H), 8.34-8.26 (m, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 7.9 Hz,2H), 7.25 (s, 1H), 7.05-6.97 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 6.80 (s,1H), 5.35 (dd, J = 12 8, 5.3 Hz, 1H), 4.52-4.36 (m, 4H), 4.30- 4.17 (m,3H), 3.96 (d, J = 14.4 Hz, 1H), 3.82 (d, J = 14.3 Hz, IH), 3.33 (s, 3H),3.19 (s, 3H), 2.97-2.85 (m, 1H), 2.76-2.67 (m, 1H)), 2.66-2.58 (m, 3H),2.34-2.18 (m, 2H), 2.17-2.10 (m, 2H), 2.04-1.86 (m, 4H), 1.85-1.76 (m,3H), 1.75-1.67 (m, 2H), 1.65-1.48 (m, 5H), 1.40-1.29 (m, 4H) J209

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(5S,8S,10aR-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2- a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2-chloro-5- fluorophenyl] butanamido)-3,3-dimethylbutanoyl]- 4-hydroxy-N- [(1S)-1-[4-(4- methyl-1,3- thiazol-5-yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride 1024.45 (300MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.54-8.30 (m, 3H), 8.18 (d, J = 7.3 Hz,1H), 7.92 (d, J = 8.9 Hz, 1H), 7.60-7.43 (m, 4H), 7.26 (s, 1H),7.03-7.01 (m, 1H), 6.80-6.76 (m, 2H), 5.00-4.93 (m, 1H), 4.55-4.44 (m,3H), 4.30-4.24 (m, 3H), 4.18-4.08 (m, 3H), 3.63-3.61 (m, 2H), 3.60-3.58(m, 4H), 2.95-2.91 (m, 3H), 2.70-2.67 (m, 3H), 2.48 (s, 3H), 2.31-2.27(m, 2H), 2.21-2.15 (m, 3H), 2.13-2.03 (m, 4H), 1.95-1.82 (m, 8H), 1.39(d, J = 7.0 Hz , 3H), 0.96 (s, 9H) J210

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2- a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2-fluoro-5- methylphenyl] butanamido)-3,3-dimethylbutanoyl]- 4-hydroxy-N- [(1S)-1-[4-(4- methyl-1,3- thiazol-5-yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride 1004.45 (400MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.49 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H),8.35 (s, 1H), 8 19 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H),7.48-7.36 (m, 4H), 7.35-7.22 (m, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.78 (s,1H), 6.61 (d, J = 6.1 Hz, 1H), 4.92 (t, J = 7.3 Hz, 1H), 4.53(d, J = 9.3Hz, 1H), 4 48 (s, 1H), 4.47-4.33 (m, 2H), 4.30-4.21 (m, 3H), 4.01 (t, J= 12.1 Hz, 3H), 3.90 (d, J = 8.9 Hz, 1H), 3.77 (d, J = 14.9 Hz, 1H),3.63 (d, J = 16.5 Hz, 3H), 3.47-3.37 (m, 1H), 3.19-3.11 (m, 1H),2.96-2.86 (m, 1H), 2.47 (s, 3H), 2.33-2.19 (m, 6H), 2.20-2.08 (m, 6H),2.07-1.89 (m, 1H), 1.88-1.65 (m, 8H), 1.60-1.45 (m, 1H), 1.38 (d, J =7.0 Hz, 3H), 0.94 (s, 9H) J211

(2S,4R)-1-[(2S)-2- (4-[3-[(2S)-2- [[(5S,8S,10aR)-3- acetyl-5-amino-6-oxo- octahydropyrrolo[1, 2- a][1,5]diazocin-8- yl]formamido]-4-carbamoylbutoxy]- 2,5- difluorophenyl] butanamido)-3,3-dimethylbutanoyl]- 4-hydroxy-N- [(1S)-1-[4-(4- methyl-1,3- thiazol-5-yl)phenyl]ethyl] pyrrolidine-2- carboxamide hydrochloride 1008.15 crudeused directly without purification J212

(5S,8S,10aR)-3- acetyl-5-amino-N- ((S)-5-amino-1-(2- chloro-3-(4-(((S)-1-((2S,4R)-4- hydroxy-2-(((S)-1- (4-(4- methylthiazol-5-yl)phenyl)ethyl) carbamoyl)- pyrrolidin- 1-yl)-3,3- dimethyl-1-oxobutan-2- yl)amino)-4- oxobutyl)-5- methylphenoxy)-5-oxopentan-2-yl)-6- oxodecahydro- pyrrolo[1,2- a][1,5]diazocine-8-carboxamide hydrochloride 1020.05. (400 MHz, DMSO-d₆) δ 9.08 (s, 1H),8.58-8.53 (m, 1H), 8.44-8.33 (m, 2H), 8.19 (d, J = 8.0 Hz, 1H), 7.88 (d,J = 9.3 Hz, 1H), 7.48-7.42 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz,2H), 7.33-7.20 (m, 1H), 6.84 (d, J = 1.8 Hz, 1H), 6.78-6.75 (m, 1H),6.73-6.67 (m, 1H), 4.98-4.87 (m, 1H), 4.57-4.34 (m, 3H), 4.28-4.20 (m,3H), 4.13-3.97 (m, 3H), 3.95-3.84 (m, 1H), 3.79-3.72 (m, 1H), 3.66-3.59(m, 2H), 3.29-3.13 (m, 2H), 2.69-2.57 (m, 2H), 2.47 (s, 3H), 2.36-2.23(m, 5H), 2.22-2.08 (m, 6H), 2.06-1,64 (m, 12H), 1.38 (d, J = 7.0 Hz,3H), 0.95 (s, 9H) J213

(2S)-2-[[(2S,11S)- 11-amino-6-[6-[1- (2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]hexyl]-12-oxo- 1- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] trideca- 4(13),5,7-trien-2-yl]formamido]-N- [(4- methanesulfonyl- phenyl)methyl] pentanediamidehydrochloride  883.40 (300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.63 (t, J =5.9 Hz, 1H), 8.50-8.43 (m, 3H), 7.85 (d, J = 7.2 Hz, 2H), 7.48 (d, J =8.0 Hz, 2H), 7.34 (s, 1H), 7.05-6.94 (m, 3H), 6.90-6.80 (m, 3H), 5.41-5.31 (m, 1H), 5.20-5.12 (m, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.27-4.14 (m,2H), 3.47-3.38 (m, 1H), 3.34 (s, 3H), 3.20 (s, 3H), 3.15-3.11 (m, 2H),2.97- 2.86 (m, 2H), 2.79-2.57 (m, 5H), 2.26-2.10 (m, 3H), 2.07- 1.96 (m,2H), 1.94-1.77 (m, 2H), 1.65-1.47 (m, 5H), 1.38- 1.28 (m, 4H) J214

(2S)-2- [[(5S,8S,10aR)-5- amino-6-oxo-3- [(1s,4s)-4-[2-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]ethyl]cyclohexanecarbonyl]- octahydropyrrolo[1, 2- a][1,5]diazocin-8-yl]formainido]-N- [(4- methanesulfonyl- phenyl)methyl] pentanediamidetrifluoroacetate  918.30 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.59 (d, J= 6.2 Hz, 1H), 8.41-8.26 (m, 3H), 7.87 (d, J = 8.1 Hz, 2H), 7.50 (dd, J= 8 4, 2.8 Hz, 2H), 7.24 (s, 1H), 7.07- 6.98 (m, 2H), 6.87 (t, J = 9.3Hz, 1H), 6.80 (s, 1H), 5.35 (dd, J = 12.6, 5.4 Hz, 1H), 4.90-4.83 (m,1H), 4.46-4.44 (m, 1H), 4.41-4.39 (m, 1H), 4.28-4.24 (m, 1H), 4.20-4 16(m, 1H), 3.99-3.88 (m, 1H), 3.87-3.75 (m, 1H), 3.33 (s, 3H), 3.20 (s,3H), 2.93-2.85 (m, 1H), 2.73- 2.59 (m, 5H), 2.42-2.32 (m, 1H), 2.26-2.18(m, 2H), 2.16- 2.09 (m, 2H), 2.04-1.87 (m, 4H), 1.84-1.70 (m, 6H), 1.67-1.43 (m, 10H)

(2S)-2-[[(5S,8S,10aR)-5-amino-3-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hexanoyl]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-N-(diphenylmethyl)pentanediamide(Intermediate J79)

A solution of tert-butylN-[(5S,8S,10aR)-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-3-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hex-5-ynoyl]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate(300 mg, 0.31 mmol) in (CF₃)₂CHOH (15.0 mL) was stirred for 4 days at65° C. under nitrogen atmosphere. The resulting mixture was cooled downto room temperature and concentrated under reduced pressure. The residuewas purified by Prep-TLC (CH₂Cl₂:MeOH=10:1) to afford the title compoundas a light yellow solid (180 mg, 64%): ¹H NMR (400 MHz, DMSO-d₄). 11.12(s, 1H), 8.74 (d, J=8.7 Hz, 1H), 8.15 (dd, J=16.0, 7.9 Hz, 1H),7.36-7.19 (m, 12H), 7.14-7.07 (m, 2H), 6.75 (d, J=12.6 Hz, 1H), 6.09(dd, J=8.5, 2.3 Hz, 1H), 5.38 (dd, J=12.8, 5.4 Hz, 1H), 4.45-4.27 (m,5H), 4.14 (d, J=7.9 Hz, 1H), 4.00-3.72 (m, 3H), 3.72-3.43 (m, 2H), 3.32(s, 3H), 2.94 (m, 2H), 2.79-2.55 (m, 2H), 2.49-2.41 (m, 2H), 2.20-1.89(m, 3H), 1.89-1.54 (m, 10H); MS (ESI, m/z): [(M+1)]⁺=872.50.

The following intermediates in Table 54 were prepared according to theabove procedure to prepare Intermediate 179.

TABLE 54 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H NMR J80

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[7-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]hept- 6-ynoyl]-6-oxo-octahydropyrrolo[1,2-a] [1,5]diazocin-8-yl] formamido]-N-(diphenylmethyl) pentanediamide 886.5 (400 MHz, DMSO-d₆) δ 11.12 (s,1H), 8.73 (dd, J = 8.5, 6.0 Hz, 1H), 8.20-8.10 (m, 1H), 7.41-7.20 (m,12H), 7.09 (d, J = 2.2 Hz, 1H), 6.74 (d, J = 12.8 Hz, 1H), 6.10 (d, J =8.4 Hz, 1H), 5.38 (dd, J = 12.8, 5.3 Hz, 1H), 4.47-4.27 (m, 3H), 4.12(s, 1H), 3.85-3.77 (m, 1H), 3.77-3.55 (m, 2H), 3.52-3.38 (m, 1H), 3.32(s, 3H), 3.27-3.15 (m, 1H), 3.05-2.80 (m, 1H), 2.80-2.57 (m, 3H), 2.48-2.26 (m, 3H), 2.23-1.40 (m, 17H). J81

(2S)-2- [[(5S,8S,10aR)-5- amino-3-[8-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2- oxo-1,3- benzodiazol-5- yl]oct-7-ynoyl]-6- oxo-octahydropyrrolo- [1,2-a][1,5]diazocin- 8-yl]formamido]-N-(diphenylmethyl) pentanediamide 900.3 (400 MHz, CDCl₃) δ 7.78-7.55 (m,1H), 7.50-7.15 (m, 9H), 7.15-6.86 (m, 2H), 6.82-6.58 (m, 1H), 6.19 (dd,J = 8.2, 4.5 Hz, 1H), 5.81 (s, 1H), 5.25 (m, 1H), 4.51 (s, 1H),4.35-4.18 (m, 1H), 4.11-3.90 (m, 1H), 3.90-3.59 (m, 2H), 3.39 (s, 3H),3.30-3.10 (m, 1H), 2.95-1.36 (m, 20H), 1.35-1.21 (m, 3H), 0.99- 0.79 (m,2H).

Tert-butylN-[(5S,8S,10aR)-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-octahydro-1H-pyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate(Intermediate K)

Step 1: 9H-fluoren-9-ylmethylN-[(S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamate. To asolution of(2S)-4-carbamoyl-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butanoicacid (synthesized according to the literature WO2007/1306) (20.0 g, 54.3mmol) and TEA (11.0 g, 110 mmol) in DMA (400 mL) were addeddiphenylmethanamine (10.9 g, 0.06 mmol) and HATU (24.8 g, 0.065 mmol) at25° C. The mixture was stirred at 25° C. for 16 h. The product wasprecipitated by the slow addition of water (200 mL) at room temperatureand was collected by filtration and washed with water (2×50.0 mL). Thesolids were triturated with acetone (100 mL) for 30 min. Afterfiltration, the filtered cake was collected and washed with acetone(2×30.0 mL). The solids were dried under vacuum to afford the titlecompound as a white solid (38.0 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ8.80 (d, J=8.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.74 (dd, J=7.5, 4.8 Hz,2H), 7.55 (d, J=8.3 Hz, 1H), 7.42 (td, J=7.5, 2.1 Hz, 2H), 7.37-7.20 (m,12H), 6.78 (s, 1H), 6.11 (d, J=8.4 Hz, 1H), 4.33-4.08 (m, 4H), 2.30-2.03(m, 2H), 1.91 (ddt, J=15.1, 10.3, 5.2 Hz, 1H), 1.79 (ddt, J=13.6, 9.2,4.9 Hz, 1H); LC/MS (ESI, m/z): [(M+1)]⁺=534.40.

The intermediates in Table 55 were prepared according to Step 1 of theprocedure to prepare Intermediate K.

TABLE 55 Characterization data for intermediates prepared according toabove. Chemical Intermediate Structure Name MS: [(M + 1)]⁺ ¹H-NMR K-1-1

tert-butyl N- [(1R)-3- carbamoyl-1- (diphenylmeth- ylcarbamoyl)-propyl]carbamate 412.15 (400 MHz, CD₃OD) δ 7.36-7.32 (m, 4H), 7.27 (dd,J = 8.6, 6.4 Hz, 6H), 6.17 (s, 1H), 4.16 (dd, J = 9.0, 5.1 Hz, 1H), 2.30(t, J = 7.6 Hz, 2H), 2.08-2.04 (m, 1H), 1.89-1.86 (m, 1H), 1.46 (s, 9H)K-1-2

tert-butyl N- [(1S)-3- carbamoyl-1- [[(4- isopropylphen- yl)methyl]carb-amoyl]propyl] carbamate 378.30 (300 MHz, DMSO-d₆) δ 8.45- 8.16 (m, 1H),7.32 (s, 1H), 7.19- 715 (m, 4H), 6.91 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H),4.25 (t, J = 5.2 Hz, 2H), 3.97-3.78 (m, 1H), 2.86 (p, J = 6.8 Hz, 1H),2.13 (d, J = 11.0 Hz, 2H), 1.96-1.64 (m, 2H), 1.40 (s, 9H), 1.19 (d, J =6.7 Hz, 6H) K-1-3

tert-butyl N- [(1S)-3- carbamoyl-1- [[(4-methane- sulfonylphenyl)-methyl]carba- moyl]propyl]- carbamate 414.05 (400 MHz, DMSO-d₆) δ 8.48(t, J = 6.1 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H),7.28 (s, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.78 (s, 1H), 4.38 (d, J = 6.0Hz, 2H), 3.91 (td, J = 8.5, 5.4 Hz, 1H), 3.19 (s, 3H), 2.11 (dt, J =8.6, 6.1 Hz, 2H), 1.87 (ddt, J = 14.4, 9.3, 5.9 Hz, 1H), 1.72 (ddd, J =15.0, 12.1, 7.5 Hz, 1H), 1.40 (s, 9H)

Step 2: (2S)-2-Amino-N-(diphenylmethyl)pentanediamide. To a stirredsolution of 9H-fluoren-9-ylmethylN-[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamate (4.00 g,7.50 mmol) in DMF (10.0 mL) was added piperidine (5.00 mL) dropwise atroom temperature under argon atmosphere. The resulting mixture wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by reverse phaseflash chromatography with the following conditions: Column: SphericalC¹⁸, 20-40 um, 330 g; Mobile Phase A: water (plus 10 mmol/L NH₄HCO₃);Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 30% B-50% B in 20min; Detector: UV 254/220 nm. The fractions containing desired productwere collected at 39% B and concentrated under reduced pressure toafford the title compound as an off-white solid (2.0 g, 86%): ¹H NMR(400 MHz, DMSO-d₆) δ 8.67 (d, J=8.6 Hz, 1H), 7.39-7.21 (m, 10H), 6.70(s, 1H), 6.10 (d, J=7.5 Hz, 1H), 3.24 (dd, J=8.3, 5.0 Hz, 1H), 2.23-2.03(m, 2H), 1.85 (d, J=5.4 Hz, 2H), 1.65-1.51 (m, 1H); LC/MS (ESI, m/z):[(M+1)]⁺=312.10.

Step 3: Benzyl(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-3-carboxylate.To a stirred solution of(5S,8S,10aR)-3-[(benzyloxy)carbonyl]-5-[(tert-butoxycarbonyl)amino]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylicacid (1.00 g, 2.17 mmol), (2S)-2-amino-N-(diphenylmethyl)pentanediamide(0.74 g, 2.38 mmol) and TEA (0.44 g, 4.33 mmol) in DMA (20.0 mL) wasadded PyBOP (1.69 g, 3.25 mmol) in portions at room temperature underair atmosphere. The resulting mixture was stirred for 16 h at roomtemperature. The reaction was quenched by the addition of water (60.0mL). The resulting mixture was extracted with EtOAc (3×50.0 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure to give the title compound as a yellow oil (1.50 g,crude): ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.13 (m, 15H), 6.19 (d, J=8.3 Hz,1H), 5.71-5.45 (m, 2H), 5.17 (s, 2H), 4.64 (dd, J=60.9, 9.1 Hz, 2H),4.38-4.18 (m, 1H), 3.77-3.50 (m, 2H), 3.35 (s, 1H), 2.50-2.29 (m, 2H),2.19 (dd, J=26.1, 16.3 Hz, 3H), 2.02-1.89 (m, 3H), 1.73-1.52 (m, 2H),1.45 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=755.25.

Step 4: Tert-butylN-[(5S,8S,10aR)-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-octahydro-1H-pyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate.To a solution of benzyl(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-3-carboxylate(10.0 g, 13.3 mmol) in THF (200 mL) was added 10% palladium on activatedcarbon (140 mg) under nitrogen atmosphere. The mixture was degassed forthree times and was hydrogenated at room temperature for 4 h using ahydrogen balloon. The resulting mixture was filtered. The filter cakewas washed with THF (3×20.0 mL). The combined filtrates was concentratedunder reduced pressure. The residue was purified by reverse phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 μm, 80 g; Eluent A: water (plus 10 mmol/L TEA); Eluent B: ACN;Gradient: 35%-55% B in 15 min; Flow rate: 50 mL/min; Detector: UV220/254 nm; desired fractions were collected at 48% B and concentratedunder reduced pressure to afford the title compound as a light yellowsolid (7.0 g, 85%): ¹H NMR (400 MHz, DMSO-d₄) δ 8.91 (d, J=7.9 Hz, 1H),8.34 (d, J=8.6 Hz, 1H), 7.40-7.18 (m, 11H), 6.78 (s, 1H), 6.09 (d, J=8.6Hz, 1H), 5.94 (d, J=7.6 Hz, 1H), 4.70-4.58 (m, 1H), 4.36 (dt, J=19.5,10.2 Hz, 2H), 4.30-4.17 (m, 1H), 3.13 (d, J=14.1 Hz, 1H), 3.02 (td,J=6.6, 3.9 Hz, 2H), 2.80 (dd, J=11.9, 6.2 Hz, 2H), 2.65 (t, J=12.9 Hz,1H), 2.47-2.23 (m, 2H), 2.02 (td, J=14.2, 12.5, 6.4 Hz, 2H), 1.91-1.64(m, 4H), 1.39 (s, 10H); LC/MS (ESI, m/z): [(M+1)]⁺=621.30.

The intermediates in Table 56 were prepared according to Step 4 of theprocedure to prepare Intermediate K.

TABLE 56 Characterization data for intermediates prepared according toabove. Intermediate Structure Chemical Name MS: [(M + 1)]⁺ ¹H-NMR K1

tert-butyl N- [(5S,8S,10aR)-8- [[(1R)-3- carbamoyl-1- (diphenylmethyl-carbamoyl)propyl]- carbamoyl]-6-oxo- octahydro-1H- pyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 621.25 (400 MHz, DMSO-d₆) δ 8.94 (d, J =8.2 Hz, 1H), 8.67 (d, J = 8.7 Hz, 1H), 7.45-7.16 (m, 11H), 6.76 (s, 1H),6.62 (d, J = 7.4 Hz, 1H), 6.14 (dd, J = 18.3, 8.7 Hz, 1H), 4.59 (d, J =6.0 Hz, 1H), 4.41-4.17 (m, 2H), 3.62 (d, J = 13.3 Hz, 1H), 3.30 (s, 2H),3.07 (d, J = 15.5 Hz, 1H), 2.93-2.77 (m, 1H), 2.72 (d, J = 12.6 Hz, 1H),2.62 (t. J = 11.8 Hz, 1H), 2.32-1.62 (m, 9H), 1.39 (s, 9H) K2

tert-butyl N- [(5S,8S,10aR)-8- [[(3S,4R)-4-[(4- bromophenyl)me-thoxy]-1- carbamoylpentan- 3-yl]carbamoyl]- 6-oxo-octahydro-1H-pyrrolo[1,2- a][1,5]diazocin-5- yl]carbamate  624.00, 626.00 (400MHz, DMSO-d₆) δ 8.41 (d, J = 9.3 Hz, 1H), 7.58-7.49 (m, 2H), 7.35-7.27(2, 3H), 7.16 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 4.71-4.26(m, 6H), 3.76-3.64 (m, 1H), 3.39 (d, J = 6.3 Hz, 1H), 3.18-3.01 (m, 1H),2.80 (dd, J = 11.9, 6.1 Hz, 1H), 2.75-2.59 (m, 2H), 2.36-2.22 (m, 1H),2.07-1.99 (m, 2H), 1.97- 1.64 (m, 3H), 1.60-1.41 (m, 2H), 1.38 (s, 9H),1.36-1.32 (m, 2H), 1.05 (d, J = 6.2 Hz, 3H) K3

tert-butyl N- [(5S,8S,10aR)-8- [[(3S,4R)-4- (benzyloxy)-1-carbamoylpentan- 3-yl]carbamoyl]- 6-oxo-octahydro- 1H-pyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate 546.35 (400 MHz, DMSO-d₆) δ 8.42 (d, J =9.3 Hz, 1H), 7.39-7.23 (m, 5H), 7.18 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H),6.68 (s, 1H), 4.68-4.57 (m, 1H), 4.56-4.40 (m, 2H), 4.39- 4.27 (m, 2H),3.75-3.63 (m, 1H), 3.39 (d, J = 7.1 Hz, 2H), 3.24- 3.08 (m, 2H),2.90-2.76 (m, 1H), 2.67 (q, J = 12.2, 11.3 Hz, 2H), 2.33-2.22 (m, 1H),2.08-1.79 (m, 4H), 1.61-1.41 (m, 2H), 1.38 (s, 9H), 1.36-1.32 (m, 2H),1.06 (d, J = 6.2 Hz, 3H) K4

tert-butyl N- [(5S,8S,10aR)-8- [(3-carbamoyl-1 [[(4- methanesulfonyl-phenyl)methyl] carbamoyl]propyl) carbamoyl]-6-oxo- octahydro-1H-pyrrolo[1,2- a][1,5]diazocin-5- yl]carbamate 623.15 (300 MHz, CDl3) δ9.04 (d, J = 7.6 Hz, 1H), 7.98-7.80 (m, 3H), 7.48 (d, J = 8.3 Hz, 2H),6.51 (s, 1H), 5.66 (s, 1H), 5.18 (d, J = 8.2 Hz, 1H), 4.93-4.86 (m, 1H),4.61- 4.19 (m, 5H), 3.43-3.35 (m, 1H), 3.17-3.09 (m, 1H), 3.02 (s, 3H),2.76-2.71 (m, 1H), 2.63-2.28 (m, 2H), 2.28-1.98 (m, 2H), 1.61- 1.48 (m,1H), 1.44 (s, 9H)

5-[(Diethoxyphosphoryl)methyl]-1H-indole-2-carboxylic acid (IntermediateL)

To a stirred solution of ethyl5-[(diethoxyphosphoryl)methyl]-1H-indole-2-carboxylate (synthesizedaccording to the literature WO2010/077589) (5.00 g, 14.8 mmol) in THF(50.0 mL) was added H₂O (50.0 mL) and LiOH (5.29 g, 221 mmol) inportions at room temperature. The resulting mixture was stirred for 16 hat room temperature. The mixture was acidified to pH 6 with aqueous HCl(1 M). The precipitated solids were collected by filtration and washedwith water (2×10.0 mL). Then it was dried in vacuum to give the titlecompound as a white solid (2.20 g, 48%): ¹H NMR (400 MHz, CD₃OD) δ 7.59(ddd, J=3.4, 1.7, 0.8 Hz, 1H), 7.42 (dq, J=8.6, 1.0 Hz, 1H), 7.24 (dt,J=8.5, 1.9 Hz, 1H), 7.13 (t, J=0.8 Hz, 1H), 4.03 (dqd, J=8.1, 7.1, 2.9Hz, 4H), 3.34 (s, 1H), 3.29 (s, 1H), 1.26 (t, J=7.1 Hz, 6H); LC/MS (ESI,m/z): [(M+1)]⁺=312.10.

2-(4-Nitrophenoxycarbonyl)-1H-indole-5-carbonylphosphonic acid(Intermediate M)

Step 1: Tert-butyl 5-bromo-1H-indole-2-carboxylate. A mixture of5-bromo-1H-indole-2-carboxylic acid (45.0 g, 188 mmol) in toluene (900mL) was heated at 120° C. under nitrogen atmosphere. To the abovemixture was added [bis(trimethyl-lambda4-oxidanyl)methyl]dimethylamine(67.2 g, 375 mmol) dropwise over 1 h at 120° C. The resulting mixturewas stirred for overnight at 120° C. The resulting mixture was cooleddown to room temperature and was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith petroleum ether/EtOAc (10:1) to afford the title compound as awhite solid (27.0 g, 49%): ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H),7.86 (d, J=1.9 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.36 (dd, J=8.8, 1.9 Hz,1H), 7.03 (dd, J=2.2, 0.9 Hz, 1H), 1.57 (s, 9H); LC/MS (ESI, m/z):[(M−1)]⁻=293.90, 295.90.

Step 2: Tert-butyl5-((diethoxyphosphoryl)carbonyl)-1H-indole-2-carboxylate. To a stirredsolution of tert-butyl 5-bromo-1H-indole-2-carboxylate (3.00 g, 10.2mmol) and diethyl phosphonate (1.40 g, 10.2 mmol) in toluene (60.0 mL)were added Pd₂(dba)₃.CHCl₃ (524 mg, 0.51 mmol), XantPhos (293 mg, 0.51mmol) and TEA (1.03 g, 10.2 mmol) in portions at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C.under CO (1.5 atm.) atmosphere. The resulting mixture was cooled down toroom temperature and was filtered. The filtered cake was washed with DCM(3×15.0 mL). The combined filtrates was concentrated under reducedpressure. The residue was purified by reverse phase flash with thefollowing conditions (Column: Spherical C¹⁸, 20-40 um, 330 g; MobilePhase A: water (plus 0.05% FA), Mobile Phase B: ACN; Flow rate: 80mL/min; Gradient (B %): 40%˜70%, 30 min; Detector: UV 254/220 nm; Rt: 35min.) to afford the title compound as a dark yellow oil (2.0 g, 52%): ¹HNMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.76 (d, J=1.7 Hz, 1H), 7.97(dd, J=8.9, 1.7 Hz, 1H), 7.63-7.57 (m, 1H), 7.37-7.34 (m, 1H), 4.23-4.15(m, 4H), 1.58 (s, 9H), 1.29 (t, J=7.0 Hz, 6H); LC/MS (ESI, m/z):[(M+1)]⁺=382.05.

Step 3: 5-((Diethoxyphosphoryl)carbonyl)-1H-indole-2-carboxylic acid. Toa stirred solution of tert-butyl5-[(diethoxyphosphoryl)carbonyl]-1H-indole-2-carboxylate (9.00 g, 23.6mmol) in DCM (180 mL) was added TFA (90.0 mL) at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 2 h at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under vacuum to afford the title compound as a brown yellowsolid (7.2 g, 94%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (s, 1H), 8.78 (d,J=1.7 Hz, 1H), 7.96 (dd, J=8.9, 1.7 Hz, 1H), 7.61-7.55 (m, 1H), 7.39(dd, J=2.1, 0.9 Hz, 1H), 4.19 (dqd, J=8.4, 7.1, 1.6 Hz, 4H), 1.29 (t,J=7.0 Hz, 6H); LC/MS (ESI, m/z): [(M+1)]⁺=326.05.

Step 4: 4-Nitrophenyl5-((diethoxyphosphoryl)carbonyl)-1H-indole-2-carboxylate. To a stirredmixture of 5-[(diethoxyphosphoryl)carbonyl]-1H-indole-2-carboxylic acid(500 mg, 1.54 mmol) and p-nitrophenol (321 mg, 2.31 mmol) in DCM (15.0mL) was added DCC (476 mg, 2.31 mmol) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 3 h at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The crude product was purified byreverse phase flash chromatography with the following conditions(Column: Spherical C¹⁸, 20˜40 um, 120 g; Mobile Phase A: water, MobilePhase B: ACN; Flow rate: 45 mL/min; Gradient (B %): 40%˜70%, 30 min;Detector: UV 254/220 nm; Rt: 32 min.) to afford the title compound as ayellow solid (300 mg, 440%): ¹H NMR (400 MHz, DMSO-d₆) 12.84 (d, J=2.2Hz, 1H), 8.88 (d, J=1.7 Hz, 1H), 8.41-8.38 (m, 2H), 8.06-8.03 (m, 1H),7.81-7.79 (m, 1H), 7.72-7.69 (m, 2H), 7.68-7.65 (m, 1H), 4.26-4.17 (m,4H), 1.31 (t, J=7.0 Hz, 6H); LC/MS (ESI, m/z): [(M−1)]⁺=444.95.

The intermediates in Table 57 were prepared according to Step 4 of theprocedure to prepare Intermediate M.

TABLE 57 Characterization data for intermediates prepared according toabove. Chemical Intermediate Structure Name MS: [(M + 1)]⁺ ¹H-NMR M-4-1

4-nitrophenyl 5- [(diethoxyphos- phoryl) difluoromethyl]-1-methylindole-2- carboxylate 483.1 ¹H NMR (400 MHz, CDCl₃) δ 8.44- 8.31(m, 2H), 8.07 (d, J = 1.9 Hz, 1H), 7.70 (dt, J = 8.8, 1.4 Hz, 1H), 7.66(d, J = 0.9 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.50-7.43 (m, 2H),4.32-4.15 (m, 4H), 4.13 (s, 3H), 1.35 (td, J = 7.1, 0.6 Hz, 6H). M-4-2

4-nitrophenyl 5- [(diethoxyphosphoryl) methyl]-1H-indole- 2-carboxylate433.1 ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 8.44-8.31 (m, 2H),7.71-7.64 (m, 2H), 7.63 (s, 1H), 7.48-7.41 (m, 2H), 7.27 (dt, J = 8.7,1.8 Hz, 1H), 5.57 (d, J = 8.0 Hz, 2H), 3.94 (dqd, J = 8.8, 7.1, 1.6 Hz,4H), 1.16 (t, J = 7.1 Hz, 6H). M-4-3

2,3,4,5,6- pentafluorophenyl 5- [(diethoxyphos- phoryl) carbonyl]-1H-indole-2-carboxylate [M − 1]⁻ = 489.9 ¹H NMR (400 MHz, DMSO-d₆) δ 13.01(s, 1H), 8.91 (d, J = 1.6 Hz, 1H), 8.06 (dd, J = 8.8, 1.7 Hz, 1H), 7.94(d, J = 1.5 Hz, 1H), 7.70-7.67 (m, 1H), 4.21 (dqd, J = 8.3, 7.0, 1.6 Hz,4H), 1.30 (t, J = 7.0 Hz, 6H).

Step 5: (2-((4-Nitrophenoxy)carbonyl)-1H-indole-5-carbonyl)phosphonicacid (Intermediate M. To a stirred solution of 4-nitrophenyl5-[(diethoxyphosphoryl)carbonyl]-1H-indole-2-carboxylate (300 mg, 0.67mmol) in DCM (10.0 mL) was added TMSI (404 mg, 2.02 mmol) dropwise atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred for 2 h at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure. The crudeproduct was purified by reverse phase flash chromatography with thefollowing conditions (Column: Spherical C¹⁸, 20˜40 um, 120 g; MobilePhase A: water, Mobile Phase B: ACN; Flow rate: 45 mL/min; Gradient (B%): 15%˜35%, 20 min; Detector: UV 254/220 nm; Rt: 20 min.) to afford thetitle compound as a yellow solid (150 mg, 570): ¹H NMR (400 MHz,DMSO-d₆) δ 12.76-12.70 (m, 1H), 8.94-8.91 (m, 1H), 8.41-8.36 (m, 2H),8.05 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (q, J=1.0 Hz, 1H), 7.72-7.67 (m, 2H),7.62 (d, J=8.8 Hz, 1H); LC/MS (ESI, m/z): [(M−1)]⁻=388.85.

The intermediates in Table 58 were prepared according to Step 5 of theprocedure to prepare Intermediate M.

TABLE 58 Characterization data for intermediates prepared according toabove. Chemical Intermediate Structure Name MS: [(M + 1)]⁺ ¹H-NMR M1

difluoro[1-methyl- 2-(4- nitrophenoxycar- bonyl)indol-5- yl]methylphos-phonic acid [M − 1]⁻ = 425.05 (400 MHz, CDCl₃) δ 8.35 (d, J = 9.1 Hz,2H), 8.11 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.59 (s, 1H), 7.49- 7.39(m, 3H), 4.10 (s, 3H). M2

[2-(4- nitrophenoxycar- bonyl)-1H-indol-5- yl]methylphos- phonic acid377.05 (400 MHz, DMSO-d₆) δ 12.16 (s, 1H), 8.41-8.35 (m, 2H), 7.70-7.64(m, 2H), 7.59 (d, J = 3.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.26 (d, J = 8.7Hz, 1H), 3.04 (d, J = 21.0 Hz, 2H). M3

2-(2,3,4,5,6- pentafluorophen- oxycarbonyl)-1H- indole-5- carbonylphos-phonic acid [M − 1]⁻ = 433.80 (400 MHz, DMSO-d₆) δ 12.91 (d, J = 2.2 Hz,1H), 8.96 (d, J = 1.5 Hz, 1H), 8.08 (dd, J = 8.9, 1.6 Hz, 1H), 7.87 (d,J = 2.0 Hz, 1H), 7.67-7.61 (m, 1H).

(2S,4R)-1-[(2S)-2-Amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamidehydrochloride (Intermediate N)

Step 1: Tert-butylN-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate. To asolution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (70.0 g,233 mmol) and 4-methylthiazole (25.5 g, 257 mmol) in DMF (500 mL) wereadded AcOK (45.8 g, 466 mmol) and Pd(OAc)₂ (5.24 g, 23.3 mmol). Afterbeing stirred for 16 h at 80° C. under nitrogen atmosphere. The reactionwas cooled down to room temperature and was quenched by the addition ofwater (200 mL). The resulting mixture was extracted with EtOAc (3×300mL). The combined organic layers were washed with brine (4×300 mL),dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with petroleum ether/EtOAc (10:1 to8:1) to afford the title compound as a light yellow solid (30.0 g, 38%):¹H NMR (400 MHz, CD₃OD) δ 8.86 (s, 1H), 7.48-7.36 (m, 4H), 4.82-4.63 (m,1H), 2.48 (s, 3H), 1.43 (s, 9H), 1.42 (d, J=6.9 Hz, 3H); LC/MS (ESI,m/z): [(M+H)]⁺=319.15.

The intermediates in Table 59 were prepared according to Step 1 of theprocedure to prepare Intermediate N.

TABLE 59 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRN-1-1

tert-butyl N-[1-[4-(4- methyl-1,3-thiazol-5- yl)phenyl]cyclopropyl]-carbamate 331.20 (400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.45-7.34 (m, 2H),7.27 (d, J = 8.2 Hz, 2H), 5.34 (s, 1H), 2.55 (s, 3H), 1.48 (m, 9H),1.34-1.21 (m, 4H).

Step 2: (1S)-1-[4-(4-methyl-1, 3-thiazol-5-yl)phenyl]ethanaminehydrochloride. To a stirred solution of tert-butylN-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamate (30.0 g,94.2 mmol) in dioxane (150 mL) was added a solution of HCl (gas) in1,4-dioxane (4 M, 100 mL) dropwise at 25° C. under nitrogen atmosphere.The resulting mixture was stirred for 3 h at 25° C. under nitrogenatmosphere. The resulting mixture was filtered. The filter cake waswashed with EtOAc (2×50.0 mL) and dried to give the title compound as ayellow solid (29.0 g, 97%): ¹H NMR (400 MHz, CD₃OD) δ 10.11 (s, 1H),7.75 (s, 4H), 4.63 (q, J=6.9 Hz, 1H), 2.67 (s, 3H), 1.73 (d, J=6.9 Hz,3H); LC/MS (ESI, m/z): [(M+H)]⁺=219.10.

The intermediates in Table 60 were prepared according to Step 2 of theprocedure to prepare Intermediate N.

TABLE 60 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRN-2-1

1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]cyclopro- pan-1-aminehydrochloride 231.15 (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 9.18-9.15 (m,3H), 7.54 (s, 4H), 2.47 (s, 3H), 1.55-1.43 (m, 2H), 1.31-1.15 (m, 2H).

Step 3: Tert-butyl (2S, 4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate. To astirred mixture of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(24.0 g, 104 mmol) and HATU (46.6 g, 123 mmol) in DMF (300 mL) wereadded (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanaminehydrochloride (24.0 g, 94.2 mmol) and DIEA (36.5 mL, 283 mmol) dropwiseat 0° C. under nitrogen atmosphere. The resulting mixture was stirredfor 4 h at 25° C. under nitrogen atmosphere. The reaction was quenchedby the addition of water (200 mL) at 0° C. The resulting mixture wasextracted with EtOAc (4×300 mL). The combined organic layers were washedwith brine (4×300 mL), dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with petroleumether/EtOAc (10:1 to 1:10) to give the title compound as a light yellowsolid (46.0 g, 960%): ¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.50-7.41(m, 4H), 5.08 (td, J=7.7, 5.6 Hz, 1H), 4.44-4.27 (m, 2H), 3.57 (dt,J=11.5, 3.7 Hz, 1H), 3.50 (dt, J=11.4, 1.9 Hz, 1H), 2.50 (s, 3H),2.30-2.18 (m, 1H), 1.95 (ddd, J=13.1, 8.6, 4.6 Hz, 1H), 1.56-1.46 (m,3H), 1.44s, 9H); LC/MS (ESI, m/z): [(M+H)]⁺=432.15.

The intermediates in Table 61 were prepared according to Step 3 of theprocedure to prepare Intermediate N.

TABLE 61 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRN-3-1

tert-butyl (2S,4R)-4- hydroxy-2-([1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]cyclopro- pyl]carbamoyl)pyrroli- dine-1-carboxylate 444.15(400 MHz, CD₃OD) δ 8.88 (s, 1H), 7.47-7.31 (m, 4H), 4.41 (tt, J = 5.8,3.1 Hz, 1H), 4.34-4.27 (m, 1H), 3.64-3.45 (m, 2H), 2.48 (s, 3H), 2.28(dddt, J = 17.1, 11.8, 8.0, 2.2 Hz, 1H), 2.09-1.97 (m, 1H), 1.38 (s,9H), 1.36-1.28 (m, 4H). N-3-2

tert-butyl (2S,4S)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl]car- bamoyl]pyrrolidine-1- carboxylate 432.15 (400 MHz,CD₃OD) δ 8.90 (s, 1H), 7.57-7.42 (m, 4H), 5.12-5.08 (m, 1H), 4.39-4.22(m, 2H), 3.69- 3.41 (m, 2H), 2.50 (s, 3H), 2.45- 2.35 (m, 1H), 1.98-1.88(m, 1H), 1.59-1.32 (m, 12H).

Step 4: (2S. 4R′)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1.3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride. Toa stirred solution of tert-butyl(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (46.0 g, 107 mmol) in dioxane (300mL) was added a solution of HCl (gas) in 1,4-dioxane (4 M, 150 mL)dropwise at 25° C. under nitrogen atmosphere. The resulting mixture wasstirred for 16 h at 25° C. under nitrogen atmosphere. The resultingmixture was filtered. The filter cake was washed with CH₂Cl₂ (3×50.0 mL)and dried to give the title compound as a light yellow solid (42.0 g,96%): ¹H NMR (400 MHz, CD₃OD) δ 10.11 (s, 1H), 7.66-7.60 (d, J=8.3 Hz,2H), 7.57 (d, J=8.3 Hz, 2H), 5.13 (q, J=7.0 Hz, 1H), 4.67-4.54 (m, 2H),3.41 (dd, J=12. 1, 3.5 Hz, 1H), 3.37-3.29 (m, 1H), 2.65 (s, 3H), 2.56(ddt, J=13.5, 7.5, 1.7 Hz, 1H), 1.98 (ddd, J=13.4, 10.6, 4.0 Hz, 1H),1.56 (d, J=7.0 Hz, 3H); LC/MS (ESI, m/z): [(M+H)]⁺=332.1.

The intermediates in Table 62 were prepared according to Step 4 of theprocedure to prepare Intermediate N.

TABLE 62 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRN-4-1

(2S,4R)-4-hydroxy-N- [1-[4-(4-methyl-1,3- thiazol-5- yl)phenyl]cyclopro-pyl]pyrrolidine-2- carboxamide hydrochloride 344.2 (400 MHz, CD₃OD) δ9.99 (s, 1H), 7.62-7.52 (m, 2H), 7.45 (d, J = 8.5 Hz, 2H), 4.63 (t, J =3.8 Hz, 1H), 4.55 (dd, J = 10.6, 7.5 Hz, 1H), 3.44 (dd, J = 12.1, 3.6Hz, 1H), 3.36-3.34 (m, 1H), 2.63 (s, 3H), 2.56 (ddt, J = 13.4, 7.5, 1.7Hz, 1H), 2.11 (ddd, J = 13.4, 10.6, 4.0 Hz, 1H), 1.42-1.36 (m, 4H).N-4-2

(2S,4S)-4-hydroxy-N- [(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl]pyr- rolidine-2-carboxamide hydrochloride 332.25 (400MHz, CD₃OD) δ 10.04 (s, 1H), 7.59 (s, 4H), 5.15 (q, J = 7.0 Hz, 1H),4.55 (ddt, J = 5.0, 3.7, 2.5 Hz, 1H), 4.46 (dd, J = 10.1, 4.7 Hz, 1H),3.42-3.37 (m, 2H), 2.73-2.66 (m, 1H), 2.64 (s, 3H), 2.27-2.03 (m, 1H),1.57 (d, J = 7.0 Hz, 3H).

Step 5: Tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-vi]-3,3-dimethyl-1-oxobutan-2-yl]carbamate.To a stirred mixture of(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoic acid (27.7 g,120 mmol) and TEA (45.3 mL, 448 mmol) in DMF (400 mL) were added(2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (40.0 g, 109 mmol) and HATU(53.7 g, 142 mmol) in portions at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 3 h at 25° C. under nitrogenatmosphere. The reaction was quenched by the addition of water (300 mL)at 25° C. The resulting mixture was extracted with EtOAc (3×300 mL). Thecombined organic layers were washed with brine (3×300 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by trituration with EtOAc(300 mL). The precipitated solids were collected by filtration andwashed with EtOAc (2×40.0 mL). This resulted in the title compound asalight yellow solid (50.0 g, 76): ¹H NMR (400 MHz, CD₃OD) δ 8.90 (s,1H), 7.50-7.36 (m, 4H), 6.40 (d, J=9.3 Hz, (H), 5.02 (p, J=7.0 Hz, 1H),4.62 (t, J=8.3 Hz, 9H), 4.46 (s, 1H), 4.34-4.27 (m, 1H), 3.87 (d, J=11.1Hz, 1H), 3.76 (dd, J=10.9, 4.0 Hz, 4H), 2.50 (s, 3H), 2.24 (dd, J=13.2,7.8 Hz, H), 2.06-1.93 (m, 1H), 1.56-1.48 (m, 3H), 1.46 (s, 9H), 1.03 (s,9H); LC/MS (ESI, m/z): [(M+H)]⁺=545.40.

The intermediates in Table 63 were prepared according to Step 5 of theprocedure to prepare Intermediate N.

TABLE 63 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRN-5-1

tert-butyl N-[(2S)-1- [(2S,4R)-4-hydroxy-2- ([1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]cyclopropyl]- carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamate 557.25 (400 MHz, CD₃OD) δ8.87 (s, 1H), 7.45-7.33 (m, 4H), 4.61 (dd, J = 9.1, 7.5 Hz, 1H), 4.52(s, 1H), 4.34- 4.28 (m, 1H), 3.90 (d, J = 11.1 Hz, 1H), 3.80 (dd, J =11.0, 3.9 Hz, 1H), 2.47 (s, 3H), 2.23 (ddt, J = 13.2, 7.7, 1.8 Hz, 1H),2.07 (ddd, J = 13.3, 9.2, 4.5 Hz, 1H), 1.47 (s, 9H), 1.42-1.24 (m, 4H),1.04 (s, 9H). N-5-2

tert-butyl N-[(2S)-1- [(2S,4S)-4-hydroxy-2- [[(1S)-1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl]car- bamoyl]pyrrolidin-1-yl]-3,3-dimethyl- 1-oxobutan-2- yl]carbamate 545.25 (400 MHz, CD₃OD) δ8.90 (s, 1H), 7.49-7.41 (m, 4H), 5.03 (qt, J = 7.1, 3.7 Hz, 1H), 4.52(dd, J = 9.2, 4.5 Hz, 1H), 4.40 (p, J = 4.6 Hz, 1H), 4.25 (s, 1H), 4.00(dd, J = 10.5, 5.0 Hz, 1H), 3.69 (dd, J = 10.4, 3.6 Hz, 1H), 2.50 (s,3H), 2.48-2.39 (m, 1H), 1.92 (dt, J = 13.3, 4.4 Hz, 1H), 1.52 (d, J =7.0 Hz, 3H), 1.46 (s, 9H), 1.04 (s, 9H).

Step 6:(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1)-1-[4-(4-methyl1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride(Intermediate N). To a stirred mixture of tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(49.0 g, 90.0 mmol) in MeOH (100 mL) and dioxane (400 mL) was added asolution of HCl (gas) in 1,4-dioxane (4 M, 200 mL) dropwise at 25° C.under nitrogen atmosphere. The resulting mixture was stirred for 16 h at25° C. under nitrogen atmosphere. The resulting mixture was concentratedunder reduced pressure. This resulted in the title compound as a lightyellow solid (50.0 g, 98%): ¹H NMR (400 MHz, CD₃OD) δ 10.10 (s, 1H),7.66-7.57 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 5.03 (q, J=7.0 Hz,1H), 4.73 (dd, J=9.5, 7.7 Hz, 1H), 4.53-4.46 (m, 1H), 4.11 (s, 1H), 3.90(dt, J=11.3, 1.6 Hz, 1H), 3.7-3.64 (m, 1H), 3.71-3.60 (m, 1H), 2.65 (s,3H), 2.35 (ddt, J=13.3, 7.7, 1.8 Hz, 1H), 1.94 (ddd, J=13.5, 9.5, 4.2Hz, 1H), 1.54 (d, J=7.0 Hz, 3H), 1.16 (s, 9H); LC/MS (ESI, m/z):[(M+H)]⁺=445.20.

The intermediates in Table 64 were prepared according to Step 6 of theprocedure to prepare Intermediate N.

TABLE 64 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMR N1

(2S,4R)-1-[(2S)-2- amino-3,3- dimethylbutanoyl]-4- hydroxy-N-[1-[4-(4-methyl-1,3-thiazol-5- yl)phenyl]cyclopropyl]- pyrrolidine-2-carboxamidehydrochloride 457.15 (400 MHz, DMS0-d₆) δ 9.11 (s, 1H), 9.01 (s, 1H),8.21 (br, 3H), 7.37-7.25 (m, 4H), 4.53 (dd, J = 9.2, 7.5 Hz, 1H), 4.38(s, 1H), 3.90 (d, J = 5.2 Hz, 1H), 3.79 (d, J = 11.0 Hz, 1H), 2.45 (s,3H), 2.09 (dd, J = 12.8, 7.7 Hz, 1H), 1.93- 1.79 (m, 1H), 1.32-1.10 (m,4H), 1.02 (s, 9H). N2

(2S,4S)-1-[(2S)-2- amino-3,3- dimethylbutanoyl]-4- hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol- 5-yl)phenyl]ethyl]pyrrol-idine-2-carboxamide hydrochloride 455.25 (400 MHz, CD₃OD) δ 10.03 (s,1H), 7.63-7.46 (m, 4H), 5.05 (q, J = 7.0 Hz, 1H), 4.62 (dd, J = 8.9, 5.7Hz, 1H), 4.41 (p, J = 5.3 Hz, 1H), 4.06 (s, 1H), 3.98 (dd, J = 10.5,5.3Hz, 1H), 3.57 (dd, J = 10.5, 4.8 Hz, 1H), 2.64 (s, 3H), 2.53 (ddd, J =13.1, 9.1, 5.5 Hz, 1H), 1.86 (dt, J = 13.0,5.5 Hz, 1H), 1.54 (d, J = 7.0Hz, 3H), 1.16 (s, 9H).

(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)phenoxy]pyrrolidine-2-carboxamidehydrochloride (Intermediate N3)

Step 1: 4-(4-Methyl-1,3-thiazol-5-yl)phenol. To a stirred mixture of4-bromophenol (20.00 g, 115.601 mmol) and 4-methylthiazole (13.75 g,138.679 mmol) in DMF (100.00 mL) was added KOAc (22.69 g, 231.202 mmol)and Pd(AcO)₂ (2.60 g, 11.581 mmol) at room temperature. The resultingmixture was stirred for 16 h at 90° C. under nitrogen atmosphere. Theresulting mixture was allowed to cool down to room temperature and wasfiltered. The filter cake was washed with EtOAc (3×200 mL). The combinedfiltrate was concentrated under reduced pressure. The residue wasdiluted with 1 N HCl (500 mL) and extracted with EtOAc (3×300 mL). Thecombined organic layers were washed with brine (2×300 mL) and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was diluted with EtOAc (20 mL) andpetroleum ether (5 mL). The precipitated solids were collected byfiltration and washed with petroleum ether (2×20 mL). This resulted inthe title compound (6 g, 27%) as a yellow solid: ¹H NMR (400 MHz,DMSO-d₆) δ 9.74 (s, 1H), 8.91 (s, 1H), 7.33-7.26 (m, 2H), 6.89-6.83 (m,2H), 2.42 (s, 3H); LC/MS (ESI, m/z): [(M+1)]⁺=192.05.

Step 2: o-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]hydroxylamine. To astirred solution of 4-(4-methyl-1,3-thiazol-5-yl)phenol (200.00 mg,1.046 mmol) in DMF (10.00 mL) was added NaH (62.74 mg, 1.569 mmol, 60%dispersion in mineral oil) in portions at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 30 min at 0° C. undernitrogen atmosphere. To the above mixture was added aminodiphenylphosphinate (365.81 mg, 1.569 mmol) in portions over 1 min at 0°C. The resulting mixture was stirred for additional 2 h at roomtemperature. The reaction was quenched with water (30 mL) at 0° C. Theresulting mixture was extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine (2×30 mL) and dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by reverse phase flash with thefollowing conditions (Column: Spherical C¹⁸ Column, 20-40 um, 120 g;Mobile Phase A: water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient: 25% B to 40% B in 25 min, 254 nm. The fractionscontaining the desired product were collected at 32% B) to afford thetitle compound (166 mg, 77%) as a brown oil: ¹H NMR (400 MHz,Methanol-d₄) δ 9.11-8.95 (m, 2H), 7.58-7.48 (m, 1H), 7.44 (dd, J=8.9,2.7 Hz, 2H), 7.29-7.22 (m, 2H), 2.50 (s, 3H); LC/MS (ESI, m/z):[(M+1)]⁺=207.15.

Step 3: Tert-butyl(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenoxy]carbamoyl]pyrrolidine-1-carboxylate.To a stirred solution of(2S,4R)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylicacid (1.67 g, 4.848 mmol) and HATU (1.84 g, 4.848 mmol) in DMF (15.00mL) was added DIEA (2.51 g, 19.441 mmol) at 25° C. The resulting mixturewas stirred for 15 min at 25° C. To the above mixture was addedo-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]hydroxylamine (1.00 g, 4.848mmol) at 25° C. The resulting mixture was stirred for additional 2 h at25° C. The resulting solution was purified by reverse phase flash withthe following conditions (Column: Spherical C¹⁸ Column, 20-40 um, 120 g;Mobile Phase A: water (0.05% NH₄HCO₃), Mobile Phase B: ACN; Flow rate:60 mL/min; Gradient: 30% B to 50% B in 25 min, 254 nm. The fractionscontaining the desired product were collected at 40% B) to afford thetitle compound (1 g, 39%) as a white solid: ¹H NMR (400 MHz,Methanol-d₄) δ 8.88 (s, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.4 Hz,2H), 4.65-4.50 (m, 2H), 4.32 (s, 1H), 4.01-3.75 (m, 2H), 2.47 (s, 3H),2.34-2.13 (m, 2H), 1.47 (s, 9H), 1.04 (s, 9H); LC/MS (ESI, m/z):[(M+1)]⁺=533.21.

Step 4:(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)phenoxy]pyrrolidine-2-carboxamidehydrochloride. To a stirred solution of tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenoxy]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(4.30 g, 8.073 mmol) in dioxane (40.00 mL) was added 4 M HCl in1,4-dioxane (20.00 mL) dropwise at 25° C. The resulting mixture wasstirred for 2 h at 25° C. The resulting mixture was concentrated underreduced pressure. This resulted in the title compound (4 g, crude) as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 9.09 (s, 1H),8.27-8.24 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 4.51(t, J=8.5 Hz, 1H), 4.42 (s, 1H), 3.95-3.93 (m, 1H), 3.84 (d, J=10.9 Hz,1H), 2.44 (s, 3H), 2.22-2.17 (m, 1H), 2.02-1.94 (m, 1H), 1.34-1.25 (m,1H), 1.12-1.06 (m, 1H), 1.02 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=433.15.

Methyl(5S,8S,10aR)-3-acetyl-5-[(tert-butoxycarbonyl)amino]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

To a solution of methyl(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-6-oxo-octahydro-1H-pyrrolo[1,2-a][1,5]diazocine-8-carboxylate(4.44 g, 13.005 mmol) in DCM (50.00 mL) were added TEA (3.95 g, 39.015mmol) and acetyl chloride (1.53 g, 19.507 mmol) at 0° C. and stirred atroom temperature for 3 hours. The reaction was quenched by the additionof sat. NaHCO₃ (100 mL) and the resulting mixture was extracted with DCM(5×100 mL). The combined organic layers were concentrated under reducedpressure. The residue was purified by reverse phase flash chromatographywith the following conditions: column, C¹⁸ silica gel; mobile phase,CH₃CN in water (plus 10 mmol/L NH₄HCO₃), 25% to 40% gradient in 15 min;Detector, UV 220/254 nm to give the title compound as a light yellowsolid (4.55 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 5.84 (d, J=6.4 Hz, 1H),4.50 (t, J=8.6 Hz, 2H), 4.17-4.13 (m, 1H), 3.97-3.83 (m, 2H), 3.77 (s,3H), 3.42-3.28 (m, 1H), 3.21 (dd, J=14.3, 10.7 Hz, 1H), 2.42-2.33 (m,1H), 2.30 (s, 3H), 2.24-1.97 (m, 3H), 1.90-1.72 (m, 2H), 1.44 (s, 9H).LC/MS (ESI, m/z): [(M+1)]⁺=384.10.

Tert-butylN-[(2S,11S)-6-bromo-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (Intermediate O)

Step 1. Methyl(2S,11S)-6-bromo-12-oxo-11-(2,2,2-trifluoroacetamido)-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-triene-2-carboxylate. A solution ofmethyl(2S,11S)-12-oxo-11-(2,2,2-trifluoroacetamido)-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-triene-2-carboxylate (10.00 g, 28.066mmol) and NBS (7.49 g, 42.099 mmol) in DMF (10.00 mL) was stirred forovernight at room temperature under nitrogen atmosphere. The resultingsolution was purified by reverse phase flash chromatography with thefollowing conditions: Column: Spherical C¹⁸, 20-40 um, 330 g; MobilePhase A: water (plus 10 mM NH₄HCO₃); Mobile Phase B: ACN; Flow rate: 80mL/min; Gradient: 5%-5% B, 10 min, 33% B-45% B gradient in 20 min;Detector: 254/220 nm. The fractions containing the desired product werecollected at 40% B and concentrated under reduced pressure to afford thetitle compound as a yellow solid (7.0 g, 57%): ¹H NMR (400 MHz, DMSO-d₆)δ 9.90 (d, J=7.9 Hz, 1H), 7.32 (dd, J=12.7, 2.0 Hz, 2H), 5.16 (dd,J=11.3, 2.9 Hz, 1H), 4.67-4.41 (m, 1H), 3.65 (s, 3H), 3.57-3.53 (m, 1H),3.43-3.37 (m, 1H), 3.18-3.12 (m, 1H), 3.1-3.00 (m, 1H), 2.14-2.11 (m,2H). LC/MS (ESI, m/z): [(M+1)]⁺=434.95, 436.95.

Step 2.(2S,11S)-6-bromo-11-[(tert-butoxycarbonyl)amino]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-triene-2-carboxylic acid. A solutionof methyl(2S,11S)-6-bromo-12-oxo-11-(2,2,2-trifluoroacetamido)-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5,7-triene-2-carboxylate (7.5 g, 17.234mmol) and aqueous LiOH (2 M, 51.70 mL, 103.404 mmol) in THF (50.00 mL)was stirred for 3 h at room temperature under nitrogen atmosphere. Thesolution was neutralized to pH 10 with HCl (1 M). To the above solutionwas added Boc₂O (4.06 mL, 18.585 mmol) at room temperature. Theresulting mixture was stirred for additional overnight at roomtemperature. The resulting solution was purified by reverse phase flashchromatography with the following conditions: Column: Spherical C¹⁸,20-40 um, 330 g; Mobile Phase A: water (plus 10 mM NH₄HCO₃); MobilePhase B: ACN; Flow rate: 80 mL/min; Gradient: 5%-5% B, 10 min 33% B-45%B gradient in 20 min; Detector: 254/220 nm. The fractions containing thedesired product were collected at 4000 B and concentrated under reducedpressure to afford the title compound as a white solid (5 g, 680): ¹HNMR (400 MHz, DMSO-d₆), 7.27-7.19 (m, 2H), 6.95 (d, J=7.7 Hz, 1H), 4.76(dd, J=10.5, 2.1 Hz, 1H), 3.99 (q, J=6.7 Hz, 1H), 3.29-3.26 (m, 1H),3.11-2.91 (m, 3H), 2.02-2.00 (m, 2H), 1.39 (s, 9H). LC/MS (ESI, m/z):[(M+1−100)]=325.05, 327.05.

The intermediates in Table 65 were prepared according to the procedureto prepare Intermediate L.

TABLE 65 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRO-2-1

(5S,8S,10aR)- 5-[(tert- butoxycarbonyl)- amino]-6-oxo- octahydro-1H-pyrrolo[1,2-a] [1,5]diazocine-8- carboxylic acid 328.15 (400 MHz, CD₃OD)δ 5.11 (dd, J = 12.1, 5.8 Hz, 1H), 4.58 (td, J = 8.7, 3.8 Hz, 2H), 3.69(dt, J = 14.4, 3.7 Hz, 1H), 3.47-3.33 (m, 2H), 3.12 (t, J = 12.3 Hz,1H), 2.56-2.44 (m, 1H), 2.34-2.10 (m, 2H), 2.08-2.00 (m, 1H), 1.86- 1.82(m, 2H), 1.47 (s, 9H). O-2-2

(5S,8S,10aR)- 3-acetyl-5- [(tert- butoxycarbonyl)- amino]-6-oxo-octahydropyrro- lo[1,2-a][1,5]- diazocine-8- carboxylic acid 370.15 (300MHz, CDCl₃) δ 5.87 (d, J = 6.9 Hz, 1H), 4.67-4.65 (m, 1H), 4.54 (t, J =8.3 Hz, 1H), 4.29-4.25 (m, 1H), 3.95-3.77 (m, 2H), 3.68-3.63 (m, 3H),3.35 (t, J = 12.5 Hz, 1H), 2.36- 2.34 (m, 2H), 2.23 (s, 3H), 2.01-1.98(s, 1H), 1.84-1.80 (m, 1H), 1.45 (s, 9H). O-2-3

(1r,4r)-4-[3- (tert-butoxy)-3- oxopropyl]cy- clohexane-1- carboxylicacid N/A (400 MHz, DMSO-d₆) δ 11.96 (s, 1H), 2.19 (t, J = 7.7 Hz, 2H),2.14-2.07 (m, 1H), 1.89-1.86 (d, J = 12.8 Hz, 2H), 1.76-1.68 (m, 2H),1.44-1.42 (m, 1H), 1.39 (s, 9H), 1.32- 1.20 (m, 2H), 1.21-1.16 (m, 1H),0.95-0.84 (m, 3H)

Step 3. Tert-butylN-[(2S,11S)-6-bromo-2-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-12-oxo-1l-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamate (Intermediate O). The titlecompound was prepared according to the procedure to prepare intermediateG and N. H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=8.4 Hz, 1H), 8.22 (d,J=7.9 Hz, 1H), 7.39-7.15 (m, 14H), 7.07 (d, J=7.9 Hz, 1H), 6.76 (s, 1H),6.08 (d, J=8.3 Hz, 1H), 5.11 (dd, J 10.7, 2.7 Hz, 1H), 4.32 (td, J=8.4,5.0 Hz, 1H), 4.09-3.95 (m, 1H), 3.43-3.40 (z, 1H), 3.12-2.94 (m, 2H),2.94-2.84 (m, 1H), 2.14-2.02 (m, 3H), 1.91-1.87 (m, 1H), 1.83-1.71 (m,1H), 1.39 (s, 9H). LC/MS (ESI, m/z): [(M+1−100)]⁺=718.10, 720.10.

The intermediates in Table 66 were prepared according to the procedureto prepare Intermediate G.

TABLE 66 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMRO-3-1

tert-butyl N- [(2S,11S)-6- bromo-2-[[(1S)-3- carbamoyl-1-[[(4-isopropylphenyl) methyl[carbamoyl] propyl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien- 11-yl]carbamate 684.40, 686.40 (400 MHz, DMSO-d₆) δ8.35 (t, J = 5.9 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.30- 7.24 (m, 3H),7.15-7.11 (m, 5H), 6.77 (s, 1H), 5.12-5.10 (m, 1H), 4.24-4.20 (m, 2H),4.08-4.00 (m, 1H), 3.45-3.41 (m, 1H), 3.15-3.01 (m, 2H), 2.97-2.74 (m,1H), 2.88-2.84 (m, 1H), 2.14-1.85 (m, 6H), 1.81-1.72 (m, 1H), 1.39 (s,9H), 1.19 (d, J = 6.9 Hz, 6H) O-3-2

tert-butyl N- [(2S,11S)-6-bromo- 2-[[(1S)-3- carbamoyl-1-[[(4-methanesulfonylphenyl) methyl]carbamoyl] propyl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-11- yl]carbamate 720.15, 722.15 (400 MHz, DMSO-d₆) δ8.56 (t, J = 6.1 Hz, 1H), 8.30 (d, J = 7.7 Hz, 1H), 7.85 (d,J = 8.1Hz,2H), 7.48 (d, J = 8.0 Hz, 2H), 7.30 (s, 1H), 7.27 (d, J = 7.8 Hz, 2H),7.13 (d, J = 8.1 Hz, 1H), 6.79 (s, 1H), 5.12 (m, 1H), 4.44-4.32 (m, 2H),4.21 (m, 1H), 4.09-4.02 (t, J = 9.2 Hz, 1H), 3.43 (m, 1H), 3.19 (s, 3H),3.11-2.95 (m, 3H), 2.14-2.09 (m, 2H), 2.04-1.88 (m, 3H), 1.80 (m, 1H),1.39 (s, 9H)

Tert-butyl 3-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]propanoate

To a stirred solution of(1r,4r)-4-[3-(tert-butoxy)-3-oxopropyl]cyclohexane-1-carboxylic acid(5.00 g, 19.505 mmol) in THF (20.00 mL) was added BH₃.THF (1 M in THF,39.01 mL, 39.01 mmol) dropwise at 0° C. under air atmosphere. Theresulting mixture was stirred for 16 h at room temperature. The reactionwas quenched with MeOH (10 mL) and stirred for 1 h at reflux. Theresulting mixture was diluted with EtOAc (150 mL). The combined organiclayers were washed with brine (3×50 mL), dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith petroleum ether/EtOAc (10:1) to afford the title compound as acolorless oil (2.33 g, 49%): ¹H NMR (400 MHz, DMSO-d₆) δ 3.76 (s, 2H),3.27-3.21 (m, 1H), 3.17 (d, J=6.3 Hz, 2H), 2.15 (t, J=7.6 Hz, 2H),1.72-1.64 (m, 5H), 1.40-1.36 (m, 2H), 1.36 (s, 9H), 1.31-1.19 (m, 2H),1.18-1.10 (m, 1H).

Methyl (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]butanoate

To a solution of methyl (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate (86.0 g, 369 mmol)and imidazole (50.2 g, 738 mmol) in DCM (1.00 L) was added TBSCl (72.3g, 480 mmol) at 25° C. and was stirred at 25° C. for 6 h. The resultingsolution was diluted with H₂O (1.00 L) and was extracted with EtOAc(3×1.00 L). The combined organic layers were washed with brine (3×1.00L), dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with petroleum ether/EtOAc (100:1 to20:1) to afford the title compound as a light yellow oil (120 g, 94%):¹H NMR (400 MHz, CDCl₃) δ 5.34-5.26 (m, 1H), 4.26 (dd, J=8.7, 3.7 Hz,1H), 4.13-4.06 (m, 1H), 3.76 (s, 3H), 1.61 (s, 9H), 1.25 (d, J=6.4 Hz,3H), 0.88 (s, 9H), 0.07 (s, 6H): LC/MS (ESI, m/z): [(M+1)]⁺=348.15.

The intermediates in Table 67 were prepared according to the aboveprocedure.

TABLE 67 Characterization data for intermediates prepared according toabove. Chemical MS: Intermediate Structure Name [(M + 1)]⁺ ¹H-NMR

Tert- butyl[(9- iodonon-7- yn-1- yl) oxy]dimethylsilane N/A (400 MHz,CDCl₃) δ 3.63 (t, J = 6.5 Hz, 2H), 2.21 (td, J = 7.1, 2.7 Hz, 2H), 1.95(t, J = 2.7 Hz, 1H), 1.61-1.49 (m, 4H), 1.48- 1.31 (m, 4H), 0.92 (s,9H), 0.07 (s, 6H)

Tert-butyl[(9-iodonon-7-yn-1-yl)oxy]dimethylsilane

Step 1. 9-[(Tert-butyldimethylsilyl)oxy]non-2-yn-1-ol. To a solution ofEtMgBr (2.8 M in THF, 20.05 mL, 56.142 mmol) in anhydrous THF (200.00mL) was added a solution of tert-butyldimethyl(oct-7-yn-1-yloxy)silane(9 g, 37.428 mmol) in THF (20 mL) at 25° C. The solution was refluxedfor 1 h and then cooled to 0° C. Paraformaldehyde (5.06 g, 56.142 mmol)was added. The mixture was refluxed for additional 1 h. Then cooled toroom temperature and stirred for 12 h. The reaction was quenched withNaHCO₃ (50 mL). The mixture was extracted with EtOAc (3×200 mL), driedwith Na₂SO₄ and filtered. The filtrate was concentrated in vacuum. Theresidue was purified by silica gel column chromatography, eluted withEtOAc in petroleum ether (0%˜30%) to afford the title compound as awhite solid (4.3 g, 42%): ¹H NMR (400 MHz, CDCl₃) δ 3.63 (t, J=6.5 Hz,2H), 2.21 (td, J=7.1, 2.7 Hz, 2H), 1.95 (t, J=2.7 Hz, 1H), 1.61-1.49 (m,4H), 1.48-1.31 (m, 4H), 0.92 (s, 9H), 0.07 (s, 6H).

Step 2. Tert-butyl[(9-iodonon-7-yn-1-yl)oxy]dimethylsilane. To asolution of imidazole (1.19 g, 17.487 mmol) and PPh₃ (4.59 g, 17.487mmol) in Et₂O (75.00 mL) and CH₃CN (25.00 mL) was slowly added I₂ (4.44g, 17.487 mmol) at 0° C. The resulting slurry was warmed to roomtemperature and then stirred for 20 min. The slurry was cooled to 0° C.To it was added dropwise a solution of9-[(tert-butyldimethylsilyl)oxy]non-2-yn-1-ol (4.30 g, 15.897 mmol) inEt₂O (20 mL) at 0° C. The solution was slowly warmed to room temperatureand then stirred for 1 h. The reaction was diluted with hexane (100 mL).Then it was washed with aqueous NaHCO₃ (100 mL), brine (100 mL), driedwith Na₂SO₄ and filtered. The filtrate was concentrated in vacuum. Theresidue was purified by silica gel column chromatography, eluted with0%˜5% EtOAc in petroleum ether to afford the title compound as a whitesolid (4 g, 66%): ¹H NMR (400 MHz, DMSO-d₄) δ 3.89 (t, J=2.5 Hz, 2H),3.57 (t, J=6.4 Hz, 2H), 2.22-2.17 (m, 2H), 1.52-1.23 (m, 9H), 0.86 (s,9H), 0.03 (s, 6H).

Tert-butyl 3-(2-bromophenyl)propanoate

To a stirred mixture of 3-(2-bromophenyl)propanoic acid (5.00 g, 21.827mmol) and Boc₂O (9.53 g, 43.654 mmol) in t-BuOH (50.00 mL) was addedDMAP (0.80 g, 6.548 mmol) at room temperature. The resulting mixture wasstirred for 4 h at room temperature. The resulting mixture wasconcentrated under reduced pressure. The crude product was purified byreverse phase flash chromatography with the following conditions:Column: Spherical C¹⁸ Column, 20-40 um, 330 g; Mobile Phase A: water(plus 0.1 M formic acid), Mobile Phase B: ACN; Flow rate: 70 mL/min;Gradient: 80% B to 95% B in 25 min; Detector: UV 254/220 nm. Thefractions containing the desired product were collected at 92% B toafford the title compound as a yellow oil (3.5 g, 56%): ¹H NMR (400 MHz,DMSO-d₄) δ 7.62-7.57 (m, 1H), 7.35-7.31 (m, 2H), 7.18-7.16 (m, 1H), 2.93(t, J=7.6 Hz, 2H), 2.54 (d, J=7.6 Hz, 2H), 1.38 (s, 9H).

(2S)-2-[[(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-6-oxo-3-[2-[(1S,4S)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-4-carbamoylbutanoicacid (Intermediate P)

Step 1: Benzyl(5S,8S,10aR)-8-[[(2S)-1-(tert-butoxy)-4-carbamoyl-1-oxobutan-2-yl]carbamoyl]-5-[tert-butoxycarbonyl)amino]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-3-carboxylate.To a stirred solution of(5S,8S,10aR)-3-[(benzyloxy)carbonyl]-5-[(tert-butoxycarbonyl)amino]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylicacid (4.00 g, 8.667 mmol) and glutamine t-butyl ester hydrochloride(2.28 g, 9.551 mmol) in DMA (40.00 mL) were added TEA (2.63 g, 25.991mmol) and PyBOP (5.41 g, 10.396 mmol) at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 1 h at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by reversephase flash chromatography with the following conditions: Column:WelFlash™ C18-I, 20-40 μm, 330 g; Eluent A: water (plus 10 mmol/L formicacid); Eluent B: ACN; Gradient: 40%-70% B in 30 min; Flow rate: 80mL/min; Detector: 220 nm; desired fractions were collected at 58% B andconcentrated under reduced pressure to afford the title compound (4.8 g,81%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=7.2 Hz,1H), 7.46-7.27 (m, 5H), 7.24-7.15 (m, 1H), 7.02-6.67 (m, 2H), 5.10 (d,J=1.7 Hz, 2H), 4.48-4.23 (m, 2H), 4.23-4.04 (m, 2H), 3.78-3.72 (m, 2H),3.54 (t, J=14.4 Hz, 2H), 3.26-3.06 (m, 2H), 2.17 (q, J=6.2, 5.0 Hz, 3H),2.05-1.62 (m, 4H), 1.48-1.28 (m, 20H); LC/MS (ESI, m/z):[(M+H)]⁺=646.25.

Step 2: Tert-butyl(2S)-2-[[(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-6-oxo-octahydro-1H-pyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-4-carbamoylbutanoate.To a solution of benzyl(5S,8S,10aR)-8-[[(2S)-1-(tert-butoxy)-4-carbamoyl-1-oxobutan-2-yl]carbamoyl]-5-[(tert-butoxycarbonyl)amino]-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-3-carboxylate(4.60 g, 7.123 mmol) in THF (200.00 mL) was added Pd/C (758.08 mg, 10%palladium on activated carbon) under nitrogen atmosphere. The mixturewas hydrogenated at room temperature for 16 h under hydrogen atmosphereusing a hydrogen balloon. After the reaction was completed, it wasfiltered through a Celite pad and concentrated under reduced pressure.This resulted in the title compound (3.7 g, 910%) as a white solid. Thecrude product was used in the next step directly without furtherpurification: ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (d, J=7.7 Hz, 1H), 7.20(d, J=6.4 Hz, 1H), 6.81-6.68 (m, 2H), 4.63-4.54 (m, 1H), 4.42-4.25 (m,2H), 4.13-3.98 (m, 1H), 3.64-3.55 (m, 1H), 3.15-3.05 (m, 1H), 2.88-2.63(m, 3H), 2.34-2.06 (m, 3H), 2.06-1.87 (m, 1H), 1.87-1.64 (m, 3H), 1.40(s, 9H), 1.37 (s, 9H), 1.35 (d, J=8.2 Hz, 3H); LC/MS (ESI, m/z):[(M+H)]⁺=512.20.

Step 3: Tert-butyl(2S)-2-[[(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-6-oxo-3-[2-[(1S,4S)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-4-carbamoylbutanoate.To a stirred solution of tert-butyl(2S)-2-[[(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-6-oxo-octahydro-1H-pyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-4-carbamoylbutanoate(695.00 mg, 1.358 mmol) and[(1S,4S)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]aceticacid (561.68 mg, 1.358 mmol) in DMA (8.00 mL) were added TEA (412.38 mg,4.075 mmol) and PyBOP (848.30 mg, 1.630 mmol) at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 1 h at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by reversephase flash chromatography with the following conditions: Column:WelFlash™ C18-I, 20-40 μm, 330 g; Eluent A: water (plus 10 mmol/L formicacid); Eluent B: ACN; Gradient: 35%-55% B in 20 min; Flow rate: 80mL/min; Detector: 220/254 nm; desired fractions were collected at 50% Band concentrated under reduced pressure to afford the title compound(950 mg, 73%) as a white solid: ¹H NMR (300 MHz, DMSO-d₄) δ 11.06 (s,1H), 8.27 (d, J=7.7 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.07-6.89 (m, 2H),6.91-6.65 (m, 2H), 6.50 (d, J=6.8 Hz, 1H), 5.33 (dd, J=12.8, 5.4 Hz,1H), 4.40 (q, J=8.7, 7.5 Hz, 2H), 4.20-3.86 (m, 2H), 3.77 (t, J=13.8 Hz,2H), 3.61-3.42 (m, 1H), 3.38-3.29 (s, 3H), 3.19-3.06 (m, 1H), 2.99-2.81(m, 2H), 2.81-2.54 (m, 6H), 2.47-2.24 (m, 2H), 2.16 (q, J=5.4, 3.0 Hz,4H), 2.06-1.87 (m, 2H), 1.86-1.56 (m, 4H), 1.44 (s, 9H), 1.39 (s, 9H),1.37-1.33 (m, 8H); LC/MS (ESI, m/z): [(M+1)]⁺=907.25.

The intermediates in Table 68 were prepared according to Step 3 of theprocedure to prepare Intermediate P

TABLE 68 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMRP-3-1

tert-butyl (2S)-2- [[(5S,8S,10aR)-5- [tert- butoxycarbonyl)amino]-6-oxo-3-[2- [(1r,4r)-4-[[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo- 1,3-benzodiazol-5- yl]methyl]cyclohexyl] yl]acetyl]-octahydropyrrolo[1, 2-a][1,5]diazocin-8- yl]formamido][-4-carbamoylbutanoate 907.45 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.28 (t, J= 8.7 Hz, 1H), 7.21 (d, J = 6.7 Hz, 1H), 7.03-6.93 (m, 2H), 6.85-6.75(m, 2H), 6.58 (d, J = 7.1 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H),4.44-4.32 (m, 2H), 4.16-4.05 (m, 2H), 3.66 (d, J = 13.3 Hz, 1H), 3.32(s, 3H), 3.28-3.20 (m, 1H), 3.18-3.05 (m, 1H), 2.98- 2.84 (m, 1H),2.77-2.58 (m, 2H), 2.49-2.46 (m, 1H), 2.38- 2.23 (m, 2H), 2.21-2.08 (m,4H), 2.05-1.93 (m, 3H), 1.93- 1.83 (m, 2H), 1.82-1.57 (m, 10H),1.43-1.33 (m, 18H), 1.02-0.87 (m, 4H) P-3-2

tert-butyl (2S)-2- [[(5S,8S,10aR)-5- [(tert- butoxycarbonyl)amino]-3-[7-[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]heptanoyl]-6- oxo- octahydropyrrolo[1,2-a][1,5]diazocin-8- yl]formamido]-4- carbamoylbutanoate 881.70 (400MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.28 (t, J = 8.4 Hz, 1H), 7.21 (d,J =14.0 Hz, 1H), 7.05-6.94 (m, 2H), 6.89-6.93 (m, 1H), 6.78 (s, 1H), 6.56(d, J = 7.0 Hz, 1H), 5.34 (dd, J = 12.7, 5.4 Hz, 1H), 4.50-4.34 (m, 2H),4.19- 4.07 (m, 2H), 3.73-3.58 (m, 2H), 3.38-3.33 (m, 2H), 3.32 (s, 3H),3.27-3.06 (m, 2H), 2.97-2.83 (m, 1H), 2.78-2.56 (m, 4H), 2.44-2.37 (m,1H), 2.16 (t, J = 7.6 Hz, 3H), 1.97- 1.86 (m, 2H), 1.85-1.71 (m, 3H),1.68-1.46 (m, 6H), 1.38 (d, J = 8.2 Hz, 18H), 1.35- 1.30 (m, 4H)

Step 4:(2S)-2-[[(5S,8S,10aR)-5-[(tert-butoxycarbonyl)aminol-6-oxo-3-[2-[(1S,4S)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-4-carbamoylbutanoicacid. To a stirred solution of tert-butyl(2S)-2-[[(5S,8S,10aR)-5-[(tert-butoxycarbonyl)amino]-6-oxo-3-[2-[(1S,4S)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-4-carbamoylbutanoate(3.80 g, 4.189 mmol) in DCM (20.00 mL) was added TFA (4.00 mL, 53.852mmol) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 4 h at room temperature under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure. The resulting mixture was diluted with DCM (10.00 mL). To theabove mixture was added TEA (1.70 g, 16.800 mmol) dropwise and Boc₂O(1.01 g, 4.628 mmol) at 0° C. The resulting mixture was stirred foradditional 16 h at room temperature. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by reversephase flash chromatography with the following conditions: Column:WelFlash™ C18-I, 20-40 μm, 330 g; Eluent A: water (plus 10 mmol/L formicacid); Eluent B: ACN; Gradient: 30%-50% B in 20 min; Flow rate: 80mL/min; Detector: 220/254 nm; desired fractions were collected at 42% Band concentrated under reduced pressure to afford the title compound(3.0 g, 80%) as a white solid: ¹H NMR (300 MHz, DMSO-d₄) δ 12.55 (s,1H), 11.08 (s, 1H), 8.29 (d, J=7.7 Hz, 1H), 7.22 (s, 1H), 7.01 (dd,J=8.9, 4.1 Hz, 2H), 6.93-6.68 (m, 2H), 6.53 (d, J=6.8 Hz, 1H), 5.35 (dd,J=12.6, 5.3 Hz, 1H), 4.48-4.30 (m, 3H), 4.26-3.99 (m, 2H), 3.89-3.71 (m,2H), 3.33 (s, 3H), 3.18-3.02 (m, 1H), 2.90 (d, J=14.9 Hz, 1H), 2.81-2.56(m, 2H), 2.42 (d, J=9.6 Hz, 1H), 2.19 (d, J=7.9 Hz, 2H), 2.02 (d, J=13.4Hz, 2H), 1.89-1.57 (m, 2H), 1.53-1.29 (m, 12H), 1.07 (d, J=1.1 Hz, 6H),1.05 (s, 9H); LC/MS (ESI, m/z): [(M+H)]⁺=851.35.

The intermediates in Table 69 were prepared according to Step 3 of theprocedure to prepare Intermediate P

TABLE 69 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMRP-4-1 694

(2S)-2- [[(5S,8S,10aR)-5- [(tert- butoxycarbonyl) amino]-6-oxo-3-[2-[(1r,4r)-4-[[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3-benzodiazol-5- yl]methyl] cyclohexyl]acetyl]- octahydropyrrolo [1,2-a][1,5]diazocin- 8-yl]formamido]- 4- carbamoylbutanoic acid 851.30 (300MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.19 (dd, J= 15.3, 7.2 Hz, 1H), 7.22-7.14 (m, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.70(d, J = 15.2 Hz, 1H), 6.55 (d, J = 7.1 Hz, 1H), 5.32 (dd, J = 12.7, 5.3Hz, 1H), 4.38 (q, J = 8.9 Hz, 2H), 4.18-4.01 (m, 2H), 3.66 (d, J = 13.4Hz, 2H), 3.31 (s, 3H), 3.17 (dd, J = 25.8, 13.1 Hz, 2H), 3.04-2.80 (m,2H), 2.77-2.57 (m, 2H), 2.47- 2.43 (m, 1H), 2.39-2.23 (m, 2H), 2.21-2.09(m, 4H), 2.04-1.87 (m, 3H), 1.86-1.54 (m, 10H), 1.37 (s, 9H), 1.01-0.84(m, 4H) P-4-2 693

(2S)-2- [[(5S,8S,10aR)-5- [(tert- butoxycarbonyl) amino]-3-[7-[1- (2,6-dioxopiperidin-3- yl)-3-methyl-2- oxo-1,3- benzodiazol-5-yl]heptanoyl]-6- oxo- octahydropyrrolo [1,2- a][1,5]diazocin-8-yl]formamido]- 4- carbamoylbutanoic acid 825.45 (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.26 (t, J = 8.8 Hz, 1H), 7.20 (d, J = 15.4 Hz, 1H),7.05-6.95 (m, 2H), 6.90-6.83 (m, 1H), 6.77 (s, 1H), 6.57 (d, J = 6.9 Hz,1H), 5.34 (dd, J = 12.7, 5.3 Hz, 1H), 4.49- 4.34 (m, 2H), 4.22-4.09 (m,2H), 3.75-3.60 (m, 2H), 3.33 (s, 3H), 3.28- 3.19 (m, 1H), 3.18-3.04 (m,1H), 2.97-2.84 (m, 1H), 2.77-2.56 (m, 4H), 2.47-2.35 (m, 2H), 2.25- 2.10(m, 3H), 2.05-1.91 (m, 3H), 1.88-1.72 (m, 3H), 1.63-1.48 (m, 6H), 1.38(s, 9H), 1.35-1.29 (m, 4H)

(2S,4R)-1-[(2S)-3,3-dimethyl-2-([1-[3-(trimethylsilyl)prop-2-yn-1-yl]cyclopropyl]formamido)butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Intermediate Q)

Step 1: Tert-butyl1-[3-(trimethylsilyl)prop-2-yn-1-yl]cyclopropane-1-carboxylate. To asolution of tert-butyl cyclopropanecarboxylate (5 g, 35.162 mmol) in THF(150.00 mL) was added LDA (16.88 mL, 42.194 mmol, 2.5 M in THF) at −78°C. under nitrogen atmosphere. The solution was stirred at −78° C. for 2h. To the above solution was added a solution of(3-bromoprop-1-yn-1-yl)trimethylsilane (8.74 g, 45.725 mmol) in THF(150.00 mL) and DMPU (60.00 mL, 498.080 mmol) dropwise at −78° C. Themixture was stirred at −78° C. for additional 2 h and then was warmed toroom temperature. The reaction was stirred at 25° C. for 16 h. Thereaction was quenched by water/ice (500 mL). The resulting mixture wasextracted with EtOAc (3×300 mL). The combined organic layers were washedwith brine (3×200 mL) and dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with petroleumether/EtOAc (50:1 to 10:1) to afford the title compound (6 g, 68%) as ared oil: ¹H NMR (400 MHz, CDCl₃) δ 2.72 (s, 2H), 1.46 (s, 9H), 1.14 (q,J=3.9 Hz, 2H), 0.94 (q, J=3.9 Hz, 2H), 0.16 (s, 9H).

Step 2: 1-[3-(Trimethylsilyl)prop-2-yn-1-yl]cyclopropane-1-carboxylicacid. To a solution of tert-butyl1-[3-(trimethylsilyl)prop-2-yn-1-yl]cyclopropane-1-carboxylate (3.00 g,11.885 mmol) in DCM (20.00 mL) was added TFA (5.00 mL) at 25° C. Themixture was stirred at 25° C. for 2 h. The resulting mixture wasconcentrated under reduced pressure to afford the crude title compound(2 g), which was used to the next step without further purification: ¹HNMR (400 MHz, CDCl₃) δ 2.69 (s, 2H), 1.49 (q, J=4.5 Hz, 2H), 0.91 (q,J=4.8, 4.4 Hz, 2H), 0.16 (s, 9H).

Step 3:(2SAR)-1-[(2S)-3,3-dimethyl-2-([1-[3-(trimethylsilyl)prop-2-yn-1-yl]cyclopropyl]formamido)butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide.To a solution of(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(2.30 g, 5.342 mmol) and1-[3-(trimethylsilyl)prop-2-yn-1-yl]cyclopropane-1-carboxylic acid (1.05g, 5.342 mmol) in DMA (57.50 mL) were added HATU (2.44 g, 6.410 mmol)and TEA (2.16 g, 21.367 mmol) at 25° C. The mixture was stirred at 25°C. for 2 h. The resulting solution was purified by Prep-HPLC with thefollowing conditions (Column: XBridge Shield RP18 OBD Column, 30×150 mm,5 um; Mobile Phase A: water (10 mmoL/L NH₄HCO₃), Mobile Phase B: ACN;Flow rate: 60 mL/min; Gradient:20 B to 55 B in 25 min; 220 nm; RT: 23min) to afford the title compound (650 mg, 20%) as a yellow solid: ¹HNMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 7.49 (t, J=5.9 Hz, 1H), 7.40-7.30(m, 4H), 6.97 (d, J=7.7 Hz, 1H), 4.76 (t, J=8.0 Hz, 1H), 4.57 (dd,J=14.9, 6.5 Hz, 1H), 4.48 (s, 1H), 4.40 (d, J=7.7 Hz, 1H), 4.32 (dd,J=14.8, 5.0 Hz, 1H), 4.16 (d, J=11.5 Hz, 1H), 3.54 (dd, J=11.4, 3.5 Hz,1H), 3.19 (s, 1H), 2.66-2.53 (m, 2H), 2.51 (s, 3H), 2.37 (d, J=18.0 Hz,1H), 2.21-2.05 (m, 1H), 1.27-1.08 (m, 3H), 0.97 (s, 9H), 0.81-0.65 (m,1H), 0.15 (s, 9H). LC/MS (ESI, m/z): [(M+1)]⁺=609.30.

Tert-butyl N-[(3S)-1-(3-bromophenyl)-5-carbamoylpent-1-yn-3-yl]carbamate(Intermediate R)

Step 1: (4S)-4-[(Tert-butoxycarbonyl)amino]hex-5-ynoate. To a stirredmixture of methyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoate(500.00 mg, 2.039 mmol) and K₂CO₃ (563.47 mg, 4.077 mmol) in MeOH (8.00mL) was added seyferth-gilbert homologation (411.20 mg, 2.140 mmol) at0° C. under air atmosphere. The resulting mixture was stirred for 2 h atroom temperature under air atmosphere. The resulting mixture wasfiltered. The filter cake was washed with CH₂Cl₂ (2×5 mL). The filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with 10% EtOAc in petroleumether to afford the title compound (260 mg, 50%) as a light yellow oil:¹H NMR (400 MHz, CDCl₃) δ 4.93-4.75 (m, 1H), 4.56-4.34 (m, 1H), 3.69 (s,3H), 2.57-2.38 (m, 2H), 2.31 (d, J=2.3 Hz, 1H), 2.01 (qd, J=7.1, 2.2 Hz,2H), 1.45 (s, 9H); LC/MS (ESI, m/z): [(M+1- 100)]⁺=142.10.

The intermediates in Table 70 were prepared according to the aboveprocedure.

TABLE 70 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMRR-1-1

benzyl 4- ethynylcyclohexane- 1- carboxylate N/A (400 MHz, Chloroform-d)δ 7.43-7.32 (m, 5H), 5.14 (d, J = 8.6 Hz, 2H), 2.41-2.24 (m, 3H),2.10-1.94 (m, 4H), 1.51- 1.38 (m, 4H)

Step 2: Methyl(4S)-6-(3-bromophenyl)-4-[(tert-butoxycarbonyl)amino]hex-5-ynoate. To astirred mixture of methyl(4S)-4-[(tert-butoxycarbonyl)amino]hex-5-ynoate (1.10 g, 4.559 mmol) and1-bromo-3-iodo-benzene (1.55 g, 5.479 mmol) in TEA (12.00 mL, 86.333mmol) and DMSO (12.00 mL) were added CuI (86.82 mg, 0.456 mmol) andPd(PPh₃)₄ (526.81 mg, 0.456 mmol) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 2 h at 80° C. undernitrogen atmosphere. The mixture was allowed to cool down to roomtemperature and was concentrated under reduced pressure. The residue waspurified by reverse phase flash chromatography with the followingconditions: Column: WelFlash™ C18-I, 20-40 um, 330 g; Eluent A: water(plus 10 mmol/L formic acid); Eluent B: ACN; Gradient: 40%-70% B in 30min; Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions werecollected at 65% B and concentrated under reduced pressure to afford thetitle compound (1.5 g, 79%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.57 (t, J=1.8 Hz, 1H), 7.46 (ddd, J=8.1, 2.0, 1.1 Hz, 1H), 7.35 (dt,J=7.7, 1.3 Hz, 1H), 7.19 (t, J=7.9 Hz, 1H), 4.95-4.80 (m, 1H), 4.80-4.61(m, 1H), 3.71 (s, 3H), 2.61-2.47 (m, 2H), 2.10 (qt, J=8.4, 3.9 Hz, 2H),1.48 (s, 9H); LC/MS (ESI, m/z): [(M+1- 100)]⁺=295.95, 297.95.

Step 3: (4S)-6-(3-Bromophenyl)-4-[(tert-butoxycarbonyl)amino]hex-5-ynoicacid. To a stirred solution of methyl(4S)-6-(3-bromophenyl)-4-[(tert-butoxycarbonyl)amino]hex-5-ynoate (1.50g, 3.785 mmol) in dioxane (15.00 mL) was added a solution of LiOH (5.00mL, 2 M in water) dropwise at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 4 h at room temperature under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure. The residue was diluted with water (10 mL). The mixture wasacidified to pH 6 with HOAc. The precipitated solids were collected byfiltration and washed with water (2×3 mL). It was dried under reducedpressure to afford the title compound (1.35 g, 89%) as a yellow solid:¹H NMR (400 MHz, DMSO-d₆) δ 7.61-7.55 (m, 2H), 7.55-7.46 (m, 1H),7.43-7.37 (m, 1H), 7.33 (t, J=7.8 Hz, 1H), 4.55-4.39 (m, 1H), 2.31-2.53(m, 2H), 1.92-1.83 (m, 2H), 1.40 (s, 9H); LC/MS (ESI, m/z):[(M+1−100)]⁺=281.90, 283.90.

The intermediates in Table 71 were prepared according to the aboveprocedure.

TABLE 71 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)] ¹H-NMR R-3-1

(4S,5R)-5-(3- bromophenoxy)- 4-[(tert- butoxycarbonyl) amino]hexanoicacid 402.05, 404.05 (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.29-7.21 (m,1H), 7.17-7.03 (m, 2H), 6.96-6.88 (m, 2H), 6.80 (d, J = 9.4 Hz, 1H),4.38 (q, J = 6.0 Hz, 1H), 2.37-2.13 (m, 2H), 1.92-1.81 (m, 1H),1.59-1.50 (m, 1H), 1.38 (s, 9H), 1.18 (d, J = 7.0 Hz, 3H) R-3-2

(S,E)-7-(4- bromopheny1)- 4-((tert- butoxycarbonyl) amino)hept-5- enoicacid 398.15, 400.15 used next step directly without purification

Step 4: Tert-butylN-[(3S)-1-(3-bromophenyl)-5-carbamoylpent-1-yn-3-yl]carbamate. To astirred solution of(4S)-6-(3-bromophenyl)-4-[(tert-butoxycarbonyl)amino]hex-5-ynoic acid(1.25 g, 3.270 mmol) and TEA (957.56 mg, 9.463 mmol) in DMA (20.00 mL)was added PyBOP (1.97 g, 3.786 mmol) at room temperature under NH₃ (g)atmosphere. The resulting mixture was stirred for 2 h at roomtemperature under NH₃ (g) atmosphere. The resulting solution waspurified by reverse phase flash chromatography with the followingconditions: Column: WelFlash™ C18-I, 20-40 um, 80 g; Eluent A: water(plus 10 mmol/L formic acid); Eluent B: ACN; Gradient: 35%-55% B in 15min; Flow rate: 50 mL/min; Detector: 220/254 nm; desired fractions werecollected at 50% B and concentrated under reduced pressure to afford thetitle compound (1.0 g, 79%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆)δ 7.64-7.56 (m, 2H), 7.42 (dt, J=7.8, 1.3 Hz, 2H), 7.34 (t, J=7.8 Hz,2H), 6.80 (s, 1H), 4.47 (q, J=7.7 Hz, 1H), 2.23 (td, J=7.4, 3.8 Hz, 2H),1.86 (q, J=7.5 Hz, 2H), 1.41 (s, 9H); LC/MS (ESI, m/z):[(M+1−100)]⁺=280.95, 292.95.

The intermediates in Table 72 were prepared according to the aboveprocedure.

TABLE 72 Characterization data for intermediates prepared according toabove. Inter- Chemical MS: mediate Structure Name [(M + 1)]⁺ ¹H-NMR R1

tert-butyl N- [(3S,4R)-4-(3- bromophenoxy)- 1- carbamoylpentan- 3-yl]carbamate 401.05, 403.05 (400 MHz, DMSO-d₆) δ 7.29- 7.19 (m, 2H),7.13-7.06 (m, 2H), 6.95-6.88 (m, 1H), 6.82- 401.05, 6.66 (m, 2H),4.40-4.34 (m, 403.05 1H), 3.57-3.50 (m, 1H), 2.16-1.99 (m, 2H),1.88-1.74 (m, 1H), 1.59-1.46 (m, 1H), 1.38 (s, 9H), 1.18 (d, J = 6.1 Hz,3H) R2

tert-butyl N- [(3S,4E)-6- (4- bromophenyl)- 1- carbamoylhex- 4-en-3-yl]carbamate 397.15, 399.15 (400 MHz, DMSO-d₆) δ 7.51-7.44 (m, 2H),7.25-7.20 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.5 Hz, 1H),6.71 (s, 1H), 5.64-5.53 (m, 1H), 5.40 (dd, J = 15.4, 6.6 Hz, 1H), 3.86(s, 1H), 3.30 (d, J = 6.9 Hz, 2H), 2.03 (t, J = 7.8 Hz, 2H), 1.60 (p, J= 7.3 Hz, 2H), 1.38 (s, 9H)

1-[4-(Propane-2-sulfonyl)phenyl]methanamine (Intermediate T)

Step 1: 4-(isopropylsulfanyl)benzonitrile. To a stirred mixture of4-sulfanylbenzonitrile (10.00 g, 73.975 mmol, 1.00 equiv) and2-bromopropane (27.30 g, 221.926 mmol, 3 equiv) in DMF (150.00 mL) wasadded K₂CO₃ (81.79 g, 591.804 mmol, 8 equiv) in portions at roomtemperature under air atmosphere. The resulting mixture was stirred for16 h at 60 degrees C. under nitrogen atmosphere. The mixture was allowedto cool down to room temperature. The reaction was monitored by LCMS.The resulting mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with brine (3×200 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EtOAc (5:1) to afford the title compound (12.7 g, 96.85%)as an orange oil; ¹H NMR (400 MHz, Chloroform-d) δ 7.59-7.51 (m, 2H),7.41-7.33 (m, 2H), 3.62-3.52 (m, 1H), 1.39 (d, J=6.7 Hz, 6H); LC/MS(ESI, m/z): [(M+H)]⁺=178.20

Step 2: 4-(propane-2-sulfonyl)benzonitrile. To a stirred mixture of4-(isopropylsulfanyl)benzonitrile (5.00 g, 28.206 mmol, 1.00 equiv) inTFA (100.00 mL) was added H₂O₂ (30%) (100 mL) dropwise at 0 degrees C.The resulting mixture was stirred for 2 h at room temperature under airatmosphere. The reaction was monitored by LCMS. The resulting mixturewas extracted with EtOAc (3×100 mL). The combined organic layers werewashed with brine (200 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure toafford the title compound (4.8 g, 81.32%) as a white solid; ¹H NMR (400MHz, Chloroform-d) δ 8.08-7.97 (m, 2H), 7.95-7.81 (m, 2H), 3.29-3.20 (m,1H), 1.31 (d, J=6.9 Hz, 6H); LC/MS (ESI, m/z): [(M+H)]⁺=209.95.

Step 3: 1-[4-(propane-2-sulfonyl)phenyl]methanamine. To a solution of4-(propane-2-sulfonyl)benzonitrile (4.80 g, 22.938 mmol, 1.00 equiv) in40 mL 7 M NH₃ in MeOH was added Ni (5 g) under nitrogen atmosphere in a250 mL round-bottom flask. The mixture was hydrogenated at roomtemperature for 16 h under hydrogen atmosphere using a hydrogen balloon,filtered through a Celite pad and concentrated under reduced pressure.The residue was purified by reverse phase Flash chromatography with thefollowing conditions: Column: WelFlash™ C18-I, 20-40 μm, 330 g; EluentA: Water; Eluent B: ACN; Gradient: 2%-20% B in 25 min; Flow rate: 80mL/min; Detector: 220/254 nm; desired fractions were collected at 12% Band concentrated under reduced pressure to afford the title compound(3.28 g, 67.04%) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.79 (d,J=8.6 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H), 3.85 (s, 2H), 3.47-3.27 (m, 1H),1.16 (dd, J=6.8, 1.2 Hz, 6H); LC/MS (ESI, m/z): [(M+H)]⁺=214.15.

EXAMPLES Example 1. Synthesis of[([4-[(1E)-1-[[(2S,11S)-2-[[(3S,4R)-1-carbamoyl-4-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)pentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2-dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl2,2-dimethylpropanoate (I-54)

To a solution of(4S,5R)-4-[[(2S,11S)-11-amino-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-2-yl]formamido]-5-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)hexanamideacetic acid (80.0 mg, 0.086 mmol) in NMP (2.00 mL) were added NMM (26.2mg, 0.26 mmol), DMAP (1.10 mg, 0.009 mmol) and 4-nitrophenyl(2E)-3-[4-[(bis[[(2,2-dimethylpropanoyl)oxy]methoxy]phosphoryl)difluoromethyl]phenyl]but-2-enoate(72.1 mg, 0.11 mmol) in acetonitrile (0.50 mL) at room temperature. Theresulting mixture was stirred at room temperature for 2 hours. Themixture was purified by Prep-HPLC with the following conditions (Column:XBridge Shield RP18 OBD Column, 5 um, 19×150 mm; Mobile Phase A: water;Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 50% B to 65% B in 7min; Detector: UV 220/254 nm. The fractions containing desired productwas collected at 6.50 min and lyophilized to afford the title compoundas a white solid (22.5 mg, 19%): ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d,J=7.8 Hz, 1H), 7.64-7.54 (m, 4H), 7.23 (d, J=6.6 Hz, 1H), 7.14-7.11 (m,2H), 7.07 (d, J=8.5 Hz, 3H), 6.96-6.85 (m, 3H), 6.72 (d, J=7.9 Hz, 1H),6.24-6.06 (m, 2H), 5.72-5.43 (m, 4H), 5.25-5.15 (m, 2H), 4.69-4.50 (m,2H), 4.40 (d, J=11.6 Hz, 1H), 3.96 (s, 1H), 3.64-3.54 (m, 6H), 3.50-3.45(m, 4H), 3.41-3.09 (m, 6H), 2.81-2.62 (m, 8H), 2.58 (s, 3H), 2.44-2.04(m, 6H), 2.00-1.85 (m, 7H), 1.24 (s, 18H), 1.20 (s, 3H); MS (ESI, m/z):[(M+1)]⁺=1368.75.

The following compounds in Table 73 were synthesized according to theabove procedure of Example 1.

Characterization Data for Exemplary STAT3 Degraders Exam- ple I-#Chemical Name MS: [(M + 1)]⁺ ¹H NMR 2 I-1[4-[(1E)-1-[[(2S,11S)-2-[[(3S,4R)- 1251.7 (400 MHz, CD₃OD) δ 8.88 (s,1H), 7.72 (d, 1-carbamoyl-4-[[4-(4-[[(2S)-1- J = 8.1 Hz, 2H), 7.55 (d, J= 8.2 Hz, 2H), 7.48 [(2S,4R)-4-hydroxy-2-([[4-(4- (d, J = 8.3 Hz, 2H),7.42 (d, J = 8.2 Hz, 2H), methyl-1,3-thiazol-5- 7.23 (d, J = 7.9 Hz,2H), 7.16-7.09 (m, 3H), yl)phenyl]methyl]carbamoyl) 7.05 (dt, J = 14.7,7.1 Hz, 2H), 6.37 (s, 1H), pyrrolidin-1-yl]-3,3-dimethyl-1- 5.15 (dd, J= 10.8, 3.4 Hz, 1H), 4.87 (s, 1H), oxobutan-2- 4.65 (d, J = 5.3 Hz, 2H),4.59-4.55 (m, 1H), yl]carbamoyl]butyl)phenyl]metho 4.54-4.42 (m, 4H),4.36 (d, J = 15.6 Hz, 1H), xy]pentan-3-yl]carbamoyl]-12- 4.05-3.95 (m,1H), 3.91 (d, J = 11.2 Hz, 1H), oxo-1- 3.81 (dd, J = 10.9, 4.0 Hz, 1H),3.65-3.52 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-1H), 3.48 (d, J = 11.0 Hz, 1H), 3.28-3.11 (m, 4(13),5,7-trien-11- 2H),3.03 (d, J = 7.3 Hz, 1H), 2.63 (s, 2H), yl]carbamoyl]prop-1-en-2-2.56-2.50 (m, 3H), 2.49 (s, 3H), 2.29-2.16yl]phenyl]difluoromethylphosphonic (m, 7H), 2.14-1.98 (m, 2H), 1.65-1.48(m, acid 4H), 1.19-1.06 (m, 3H), 1.04 (s, 9H). 3 I-2[([4-[(1E)-1-[[(2S,11S)-2- 1480.9 (400 MHz, CDCl₃) δ 8.71 (s, 1H),7.70-7.58 [[(3S,4R)-1-carbamoyl-4-[[4-(4- (m, 3H), 7.54 (d, J = 8.2 Hz,2H), 7.43-7.31 [[(2S)-1-[(2S,4S)-4-hydroxy-2- (m, 4H), 7.31-7.20 (m,3H), 7.17-7.00 (m, ([[4-(4-methyl-1,3-thiazol-5- 5H), 6.87 (dd, J =19.1, 7.7 Hz, 2H), 6.15- yl)phenyl]methyl]carbamoyl) 6.02 (m, 2H), 5.90(s, 1H), 5.76 (ddd, J = pyrrolidin-1-yl]-3,3-dimethyl-1- 12.4, 5.0, 2.0Hz, 2H), 5.68 (ddd, J = 12.3, oxobutan-2- 5.0, 1.8 Hz, 2H), 5.19 (dd, J= 9.7, 2.9 Hz, yl]carbamoyl]butyl)phenyl]methoxy] 1H), 5.02 (s, 1H),4.72-4.50 (m, 5H), 4.49- pentan-3-yl]carbamoyl]-12- 4.38 (m, 2H), 4.32(dd, J = 15.0, 5.0 Hz, 1H), oxo-1- 4.01-3.89 (m, 2H), 3.83 (d, J = 10.9Hz, 1H), azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-3.64-3.55 (m, 1H), 3.43-3.26 (m, 3H), 3.18- 4(13),5,7-trien-11- 3.07 (m,1H), 2.63-2.47 (m, 8H), 2.33 (d, J = yl]carbamoyl]prop-1-en-2- 6.4 Hz,2H), 2.28-2.16 (m, 3H), 2.14-2.00 yl]phenyl]difluoromethyl([(2,2- (m,3H), 1.98-1.87 (m, 1H), 1.80 (dq, J = dimethylpropanoyl)oxy]methoxy)20.5, 6.5 Hz, 1H), 1.69-1.52 (m, 4H), 1.24- phosphoryl)oxy]methyl 2,2-1.03 (m, 21H), 0.94 (s, 9H). dimethylpropanoate 4 I-3[([4-[(1E)-1-(2S,11S)-2- 1280.9 (400 MHz, CDCl₃) δ 8.67 (d, J = 7.3 Hz,1H), [[(3S,4R)-1-Carbamoyl-4-[(4-[4- 7.65-7.53 (m, 4H), 7.26 (d, J = 2.5Hz, 1H), [1-(2,6-dioxopiperidin-3-yl)-3- 7.14 (d, J = 7.8 Hz, 1H),7.11-6.91 (m, 6H), methyl-2-oxo-1,3-benzodiazol-4- 6.87 (d, J = 7.9 Hz,1H), 6.69 (d, J = 7.8 Hz, yl]butyl]phenyl)methoxy]pentan- 1H), 6.18 (d,J = 12.3 Hz, 1H), 6.04 (d, J = 3-yl]carbamoyl]-12-oxo-1- 8.8 Hz, 1H),5.72-5.60 (m, 4H), 5.25-5.10 azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- (m, 2H), 5.03 (s, 1H), 4.62 (d, J = 11.3 Hz,4(13),5,7-trien-11- 2H), 4.41 (dd, J = 11.6, 8.0 Hz, 1H), 3.96 (s,yl]carbamoyl]prop-1-en-2- 1H), 3.59 (q, J = 6.3 Hz, 1H), 3.55-3.46 (m,yl]phenyl]difluoromethyl([(2,2- 3H), 3.43-3.24 (m, 3H), 3.14 (d, J = 7.4Hz, dimethylpropanoyl)oxy]methoxy) 1H), 2.97-2.71 (m, 5H), 2.63 (t, J =7.0 Hz, phosphoryl)oxy]methyl 2,2- 2H), 2.58-2.48 (m, 3H), 2.39 (d, J =7.2 Hz, dimethylpropanoate 1H), 2.23-1.94 (m, 5H), 1.86-1.58 (m, 8H),1.24-1.04 (m, 20H). 5 I-4 [([4-[(1E)-1-[[(2S,11S)-2- 1438.9 (400 MHz,CDCl₃) δ 8.74 (s, 1H), 7.63 (d, J = [[(3S,4R)-1-carbamoyl-4-[[4- 8.1 Hz,2H), 7.55 (d, J = 8.2 Hz, 2H), 7.46 ([[(2S)-1-[(254R)-4-hydroxy-2- (s,1H), 7.39-7.30 (m, 6H), 7.21 (d, J = 7.7 ([[4-(4-methyl-1,3-thiazol-5-Hz, 2H), 7.14-6.92 (m, 5H), 6.23-6.13 (m, yl)phenyl]methyl]carbamoyl)2H), 5.92 (s, 1H), 5.77 (dt, J = 12.5, 5.2 Hzpyrrolidin-1-yl]-3,3-dimethyl-1- 2H), 5.68 (ddd, J = 12.5, 5.1, 1.4 Hz,2H), oxobutan-2- 5.18 (s, 2H), 4.72-4.58 (m, 1H), 4.58 (s, 2H),yl]carbamoyl]methyl)phenyl] 4.58-4.46 (m, 3H), 4.44-4.30 (m, 3H), 4.00methoxy]pentan-3-yl]carbamoyl]-12- (d, J = 11.2 Hz, 2H), 3.92 (s, 1H),3.69-3.57 oxo-1- (m, 3H), 3.48 (s, 2H), 3.43 (d, J = 6.1 Hz,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1H), 3.38-3.24(m, 3H), 3.08 (d, J = 7.7 Hz, 4(13),5,7-trien-11- 2H), 2.59-2.51 (m,2H), 2.46 (ddd, J = 12.9, yl]carbamoyl]prop-1-en-2- 8.0, 4.6 Hz, 2H),2.36 (d, J = 13.7 Hz, 1H), yl]phenyl]difluoromethyl([(2,2- 2.16-2.04 (m,1H), 2.03 (s, 2H), 1.90 (s, 1H), dimethylpropanoyl)oxy]methoxy) 3H),0.88 (s, 9H). phosphoryl)oxy]methyl 2,2- dimethylpropanoate 6 I-5[([4-[(1E)-1-[[(2S,11S)-2- 1296.9 (400 MHz, CDCl₃) δ 9.53 (d, J = 8.5Hz, 1H), [[(3S,4R)-1-carbamoyl-4-[[4-(3- 7.68-7.50 (m, 4H), 7.26-7.12(m, 3H), 7.07 [[1-(2,6-dioxopiperidin-3-yl)-3- (d, J = 4.1 Hz, 1H),7.06-6.95 (m, 3H), 6.97- methyl-2-oxo-1,3-benzodiazol-4- 6.89 (m, 3H),6.87 (dd, J = 16.8, 8.4 Hz, 2H), yl]methoxy]propyl)phenyl]methoxy] 6.23(d, J = 8.4 Hz, 1H), 5.95 (d, J = 7.2 Hz, pentan-3-yl]carbamoyl]-12-1H), 5.83-5.61 (m, 4H), 5.36-5.06 (m, 3H), oxo-1- 4.83 (dd, J = 24.2,12.0 Hz, 1H), 4.62-4.52 azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- (m, 3H), 4.36 (t, J = 12.2 Hz, 1H), 3.92 (t,4(13),5,7-trien-11- J = 10.5 Hz, 1H), 3.75-3.64 (m, 3H), 3.60-3.48yl]carbamoyl]prop-1-en-2- (m, 1H), 3.48-3.17 (m, 4H), 3.17-3.02 (m,yl]phenyl]difluoromethyl([(2,2- 2H), 2.97-2.70 (m, 3H), 2.68-2.53 (m,5H), dimethylpropanoyl)oxy]methoxy) 2.37 (d, J = 13.2 Hz, 1H), 2.26-2.13(m, 2H), phosphoryl)oxy]methyl 2,2- 2.15-2.00 (m, 2H), 2.01-1.74 (m,3H), 1.24 dimethylpropanoate (s, 18H), 1.22-1.14 (m, 4H). 7 I-6[([4-[(1E)-1-[[(2S,11S)-2- 1294.8 (400 MHz, CDCl₃) δ 8.89 (d, J = 6.8Hz, 1H), [[(3S,4R)-1-carbamoyl-4-[(4-[5- 7.61 (d, J = 8.1 Hz, 2H), 7.54(dd, J = 8.4, [1-(2,6-dioxopiperidin-3-yl)-3- 3.0 Hz, 2H), 7.26 (dd, J =7.9, 4.6 Hz, 2H), methyl-2-oxo-1,3-benzodiazol-4- 7.16-6.92 (m, 7H),6.90-6.81 (m, 2H), 6.70 yl]pentyl]phenyl)methoxy]pentan- (t, J = 7.5 Hz,1H), 6.16 (d, J = 11.5 Hz, 1H), 3-yl]carbamoyl]-12-oxo-1- 5.97 (s, 1H),5.76 (dd, J = 12.5, 5.0 Hz, 2H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 5.68 (dd, J = 12.4, 5.0 Hz, 2H), 5.27-5.12 (m,4(13),5,7-trien-11- 2H), 5.07 (s, 1H), 4.65-4.53 (m, 2H), 4.43 (d,yl]carbamoyl]prop-1-en-2- J = 11.6 Hz, 1H), 3.97 (t, J = 10.5 Hz, 1H),yl]phenyl]difluoromethyl([(2,2- 3.61-3.49 (m, 4H), 3.43-3.25 (m, 3H),3.13 dimethylpropanoyl)oxy]methoxy) (d, J = 7.6 Hz, 1H), 2.98-2.67 (m,5H), 2.63- phosphoryl)oxy]methyl 2,2- 2.48 (m, 5H), 2.37 (d, J = 13.5Hz, 1H), 2.23- dimethylpropanoate 2.02 (m, 4H), 2.02-1.84 (m, 2H), 1.79(dt, J = 13.4, 6.0 Hz, 1H), 1.63-1.51 (m, 3H), 1.41 (t, J = 6.9 Hz, 2H),1.24-1.04 (m, 21H). 8 I-7 [([4-[(1E)-1-[[(2S,11S)-2- 1465.6 (400 MHz,CDCl₃) δ 9.00 (s, 1H), 7.63 (d, [[(3S,4R)-1-carbamoyl-4-[[4-(3- J = 8.2Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.38- [[(2S)-1-[(2S,4R)-4-hydroxy-2-7.23 (m, 5H), 7.16-7.00 (m, 6H), 6.92 (d, J =([[4-(4-methyl-1,3-thiazol-5- 9.2 Hz, 1H), 6.39 (s, 1H), 6.15 (s, 1H),5.96 yl)phenyl]methyl]carbamoyl) (s, 1H), 5.82-5.64 (m, 4H), 5.21 (d, J= 9.2 pyrrolidin-1-yl]-3,3-dimethyl-1- Hz, 2H), 4.70 (t, J = 8.0 Hz,1H), 4.62 (d, oxobutan-2- J = 11.2 Hz, 2H), 4.59 (d, J = 5.8 Hz, 1H),4.53 yl]carbamoyl]propyl)phenyl] (d, J = 7.9 Hz, 2H), 4.37 (dd, J =14.5, 6.8 methoxy]pentan-3-yl]carbamoyl]-12- Hz, 2H), 4.12 (d, J = 11.3Hz, 1H), 3.94 (s, oxo-1- 2H), 3.62-3.50 (m, 3H), 3.36-3.20 (m, 4H),azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 3.11 (d, J = 7.3Hz, 1H), 2.61-2.50 (m, 6H), 4(13),5,7-trien-11- 2.48 (s, 2H), 2.32 (s,1H), 2.19-2.12 (m, 1H), yl]carbamoyl]prop-1-en-2- 2.11-1.93 (m, 6H),1.89 (s, 3H), 1.86 (d, J = yl]phenyl]difluoromethyl([(2,2- 7.3 Hz, 1H),1.25 (s, 18H), 1.24-1.05 (m, dimethylpropanoyl)oxy]methoxy) 3H), 0.96(s, 9H). phosphoryl)oxy]methyl 2,2- dimethylpropanoate 9 I-8(2S,4R)-1-[(2S)-2-[5-[4- 1480.3 (400 MHz, CD₃OD) δ 8.95 (s, 1H), 7.99(d, ([[(2R,3S)-3-[[(2S,11S)-11-amino- J = 9.4 Hz, 1H), 7.69 (d, J = 8.3Hz, 2H), 7.63 12-oxo-1- (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2H),7.43 (d, J =8.2 Hz, 2H), 7.24 (d, J = 7.9 4(13),5,7-trien-2-l]formamido]-5- Hz, 2H),7.13-7.07 (m, 3H), 7.06 (dt, J = carbamoylpentan-2- 14.7, 7.0 Hz, 2H),6.40 (s, 1H), 5.75-5.53 (m, yl]oxy]methyl)phenyl]pentanamido]- 4H), 5.16(dd, J = 10.8, 3.3 Hz, 1H), 4.69- 3,3-dimethylbutanoyl]-4- 4.62 (m, 2H),4.57 (t, J = 8.3 Hz, 2H), 4.54- hydroxy-N-[[4-(4-methyl-1,3- 4.45 (m,3H), 4.37 (d, J = 7.6 Hz, 1H), 4.00 thiazol-5- (s, 1H), 3.91 (d, J =11.0 Hz, 1H), 3.81 (dd, yl)phenyl]methyl]pyrrolidine-2- J = 10.9, 3.8Hz, 1H), 3.59-3.45 (m, 2H), 3.25- carboxamide 2.98 (m, 3H), 2.63 (s,1H), 2.56 (d, J = 1.3 Hz, 2H), 2.49 (s, 3H), 2.33-2.20 (m, 7H),2.13-1.99 (m, 2H), 1.65 (m, 6H), 1.23 (s, 18H), 1.20-06 (m, 3H), 1.04(s, 9H). 10 I-9 [([4-[(1E)-1-[[(2S,11S)-2- 1310.9 (400 MHz, CDCl₃) δ8.95 (d, J = 7.6 Hz, 1H), [[(3S,4R)-1-carbamoyl-4-[[4-(2- 7.62 (d, J =8.3 Hz, 2H), 7.59-7.51 (m, 2H), [3-[1-(2,6-dioxopiperidin-3-yl)-3- 7.28(s, 2H), 7.20 (t, J = 7.9 Hz, 2H), 7.15- methyl-2-oxo-1,3-benzodiazol-4-6.99 (m, 5H), 6.96 (td, J = 7.8, 3.0 Hz, 1H),yl]propoxy]ethyl)phenyl]methoxy] 6.80 (dd, J = 14.0, 7.8 Hz, 1H), 6.69(d, J = pentan-3-yl]carbamoyl]-12-oxo- 7.8 Hz, 1H), 6.20 (s, 1H), 6.14(s, 1H), 5.76 1- (dd, J = 12.5, 5.0 Hz, 2H), 5.68 (dd, J = 12.4,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 5.0 Hz, 2H),5.32-5.04 (m, 3H), 4.60 (d, J = 4(13),5,7-trien-11- 10.6 Hz, 2H), 4.40(dd, J = 11.4, 5.0 Hz, 1H), yl]carbamoyl]prop-1-en-2- 3.95 (s, 1H),3.64-3.55 (m, 3H), 3.52-3.40 yl]phenyl]difluoromethyl([(2,2- (m, 5H),3.39-3.21 (m, 3H), 3.13 (d, J = 7.7 dimethylpropanoyl)oxy]methoxy) Hz,1H), 3.02-2.66 (m, 7H), 2.58-2.49 (m, phosphoryl)oxy]methyl 2,2- 3H),2.39 (d, J = 13.8 Hz, 1H), 2.22-2.08 (m, dimethylpropanoate 4H),2.02-1.93 (m, 1H), 1.87 (q, J = 6.5 Hz, 2H), 1.79 (d, J = 11.8 Hz, 1H),1.24-1.06 (m, 21H). 12 I-10 [([4-[(1E)-1-[[(2S,11S)-2- 1324.9 (400 MHz,CDCl₃) δ 7.62 (d, J = 8.2 Hz, 2H), [[(3S,4R)-1-carbamoyl-4-[[4-(3- 7.55(d, J = 8.2 Hz, 2H), 7.28-7.22 (m, 2H),[3-[1-(2,6-dioxopiperidin-3-yl)-3- 7.15 (dd, J = 7.8, 5.7 Hz, 2H),7.12-6.93 (m, methyl-2-oxo-1,3-benzodiazol-4- 5H), 6.92-6.82 (m, 2H),6.74-6.64 (m, 1H), yl]propoxy]propyl)phenyl]methoxy] 6.21-6.13 (m, 1H),6.00 (d, J = 9.5 Hz, 1H), pentan-3-yl]carbamoyl]-12- 5.76 (dd, J = 12.5,5.0 Hz, 2H), 5.68 (dd, J = oxo- 1- 12.4, 5.0 Hz, 2H), 5.28-5.04 (m, 3H),4.68- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 4.55 (m,2H), 4.43 (d, J = 11.6 Hz, 1H), 4.04- 4(13),5,7-trien-11- 3.92 (m, 1H),3.67 (d, J = 2.6 Hz, 3H), 3.63- yl]carbamoyl]prop-1-en-2- 3.55 (m, 2H),3.51-3.27 (m, 7H), 3.12 (d, J = yl]phenyl]difluoromethyl([(2,2- 17.6 Hz,1H), 3.07-2.98 (m, 2H), 2.95-2.79 dimethylpropanoyl)oxy]methoxy) (m,1H), 2.79-2.61 (m, 3H), 2.61-2.54 (m, phosphoryl)oxy]methyl 2,2- 3H),2.38 (d, J = 13.7 Hz, 1H), 2.27-2.00 (m, dimethylpropanoate 5H),2.01-1.73 (m, 6H), 1.27-1.03 (m, 21H). 13 I-11[([4-[(1E)-1-[[(2S,11S)-2- 1423.9 (400 MHz, CDCl₃) δ 8.77 (s, 1H), 7.73(d, [[(3S,4R)-1-carbamoyl-4-[(4- J = 7.9 Hz, 2H), 7.66-7.60 (m, 2H),7.56 (d, [[(2S)-1-[(2S,4R)-4-hydroxy-2- J = 8.2 Hz, 2H), 7.39-7.11 (m,6H), 7.04-6.93 ([[4-(4-methyl-1,3-thiazol-5- (m, 4H), 6.85 (t, J = 9.5Hz, 2H), 6.18 (s, 1H), yl)phenyl]methyl]carbamoyl) 5.89 (s, 1H), 5.76(dt, J = 12.4, 5.3 Hz, 2H), pyrrolidin-1-yl]-3,3-dimethyl-1- 5.67 (ddd,J = 12.4, 5.0, 3.4 Hz, 2H), 5.24- oxobutan-2- 5.00 (m, 2H), 4.76 (d, J =8.8 Hz, 1H), 4.72- yl]carbamoyl]phenyl)methoxy] 4.50 (m, 5H), 4.50-4.31(m, 2H), 4.10 (d, J = pentan-3-yl]carbamoyl]-12-oxo-1- 11.3 Hz, 1H),3.94 (d, J = 10.3 Hz, 1H), 3.69 azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- (dd, J = 11.2, 3.7 Hz, 1H), 3.58 (dd, J = 6.5,4(13),5,7-trien-11- 4.1 Hz, 1H), 3.45-3.20 (m, 3H), 3.16-3.01yl]carbamoyl]prop-1-en-2- (m, 2H), 2.63-2.41 (m, 7H), 2.42-2.28 (m,yl]phenyl]difluoromethyl([(2,2- 2H), 2.18-1.94 (m, 4H), 1.94-1.67 (m,2H), dimethylpropanoyl)oxy]methoxy) 1.24-1.04 (m, 21H), 1.02 (s, 9H).phosphoryl)oxy]methyl 2,2- dimethylpropanoate 14 I-12[([4-[(1E)-1-[[(2S,11S)-2- 1451.9 (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.63(d, [[(3S,4R)-1-Carbamoyl-4-[[4-(2- J = 8.1 Hz, 2H), 7.54 (d, J = 8.1Hz, 2H), 7.42- [[(2S)-1 -(2S,4R)-4-hydroxy-2- 7.30 (m, 5H), 7.25 (s,1H), 7.14-7.06 (m, ([[4-(4-methyl-1,3-thiazol-5- 4H), 7.05 (d, J = 6.6Hz, 1H), 6.89 (d, J = yl)phenyl]methyl]carbamoyl) 14.1 Hz, 2H), 6.23 (d,J = 8.7 Hz, 1H), 6.09 pyrrolidin-1-yl]-3,3-dimethyl-1- (s, 1H), 5.88 (s,1H), 5.76 (dt, J = 12.4, 5.3 oxobutan-2- Hz, 2H), 5.67 (dd, J = 12.4,5.0 Hz, 2H), 5.18 yl]carbamoyl]ethyl)phenyl] (d, J = 8.3 Hz, 1H), 4.99(s, 1H), 4.68 (t, J = methoxy]pentan-3-yl]carbamoyl]-12- 7.9 Hz, 1H),4.60 (t, J = 10.4 Hz, 2H), 4.56- oxo-1- 4.49 (m, 3H), 4.44-4.31 (m, 2H),4.02 (d, J = azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-11.2 Hz, 1H), 3.96 (d, J = 11.2 Hz, 1H), 3.69- 4(13),5,7-trien-11- 3.53(m, 3H), 3.42-3.25 (m, 3H), 3.11 (d, J = yl]carbamoyl]prop-1-en-2- 7.4Hz, 1H), 2.89 (dt, J = 14.7, 7.4 Hz, 1H),yl]phenyl]difluoromethyl([(2,2- 2.78 (dt, J = 14.1, 7.2 Hz, 1H), 2.56(s, 3H), dimethylpropanoyl)oxy]methoxy) 2.52 (s, 3H), 2.49-2.40 (m, 2H),2.39-2.31 phosphoryl)oxy]methyl 2,2- (m, 1H), 2.19-1.98 (m, 5H),1.84-1.62 (m, dimethylpropanoate 3H), 1.31-1.16 (m, 21H), 0.89 (s, 9H).15 I-13 [([4-[(1E)-1-[[(2S,11S)-2- 1482.8 (400 MHz, CDCl₃) δ 8.69 (s,1H), 7.66 (t, [[(3S,4R)-1-carbamoyl-4-([4-[2- J = 5.9 Hz, 1H), 7.64-7.57(m, 2H), 7.53 (d, ([[(2S)-1-[(2S,4R)-4-hydroxy-2- J = 8.2 Hz, 2H),7.42-7.30 (m, 4H), 7.29 (t, ([[4-(4-methyl-1,3-thiazol-5- J = 3.9 Hz,2H), 7.22 (s, 2H), 7.15-6.98 (m, yl)phenyl]methyl]carbamoyl) 4H), 6.93(d, J = 6.1 Hz, 1H), 6.86 (d, J = 9.2 pyrrolidin-1-yl]-3,3-dimethyl-1-Hz, 1H), 6.10 (s, 2H), 5.76 (dt, J = 12.4, 5.1 oxobutan-2- Hz, 2H), 5.68(dd, J = 12.5, 5.1 Hz, 2H), 5.21 yl]carbamoyl]methoxy)ethyl] (dd, J =8.0, 4.7 Hz, 2H), 4.69 (t, J = 8.1 Hz, phenyl]methoxy)pentan-3- 1H),4.60 (d, J = 11.3 Hz, 2H), 4.56-4.47 (m, yl]carbamoyl]-12-oxo-1- 3H),4.45-4.30 (m, 2H), 4.05 (d, J = 11.3 Hz, azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca- 1H), 3.90 (d, J = 15.1 Hz, 2H), 3.77 (d, J =4(13),5,7-trien-11- 7.2 Hz, 1H), 3.73-3.51 (m, 4H), 3.34 (ddd,yl]carbamoyl]prop-1-en-2- J = 15.8, 11.8, 6.2 Hz, 1H), 3.27-3.16 (m,2H), yl]phenyl]difluoromethyl([(2,2- 3.11 (d, J = 8.6 Hz, 1H), 2.86 (t,J = 6.5 Hz, dimethylpropanoyl)oxy]methoxy) 2H), 2.66-2.53 (m, 3H), 2.51(s, 3H), 2.44- phosphoryl)oxy]methyl 2,2- 2.29 (m, 2H), 2.20-2.02 (m,5H), 1.92 (dd, dimethylpropanoate J = 7.3, 4.3 Hz, 1H), 1.80-1.66 (m,1H), 1.24 (s, 18H), 1.19-1.06 (m, 3H), 0.97 (s, 9H). 16 I-14[4-[(1E)-1-[[(2S,11S)-2-[[(3S,4R)- 1267.8 (400 MHz, CD₃OD) δ 9.02 (s,1H), 7.64-7.54 1-carbamoyl-4-([4-[3-([[(2S)-1- (m, 4H), 7.52-7.45 (m,2H), 7.44-7.37 (m, [2S,4R)-4-hydroxy-2-([[4-(4- 2H), 7.22 (d, J = 7.9Hz, 2H), 7.22-7.13 (m, methyl-1,3-thiazol-5- 2H), 7.12 (d, J = 7.3 Hz,1H), 7.10-6.99 (m, yl)phenyl]methyl]carbamoyl) 2H), 6.38 (d, J = 1.6 Hz,1H), 5.16 (dd, J = pyrrolidin-1-yl]-3,3-dimethyl-1- 10.8, 3.3 Hz, 1H),4.73 (s, 1H), 4.68-4.51 (m, oxobutan-2- 3H), 4.48 (d, J = 3.6 Hz, 2H),4.35 (d, J = yl]carbamoyl]methoxy)propyl] 15.5 Hz, 1H), 4.06-3.92 (m,3H), 3.90 (d, J = phenyl]methoxy)pentan-3- 11.1 Hz, 2H), 3.82 (m, 4H),3.60-3.43 (m, yl]carbamoyl]-12-oxo-1- 5H), 3.27-3.11 (m, 1H), 2.75 (t, J= 7.6 Hz, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2H),2.57-2.48 (m, 1H), 2.45 (s, 3H), 2.33- 4(13),5,7-trien-11- 2.27 (m, 1H),2.26 (s, 3H), 2.23 (s, 1H), 2.11 yl]carbamoyl]prop-1-en-2- (ddd, J =13.4, 9.3, 4.3 Hz, 1H), 1.95 (s, 2H), yl]phenyl]difluoromethylphosphonic2.02-1.89 (m, 1H), 1.72-1.61 (m, 1H), 1.19- acid 1.10 (m, 3H), 1.06 (s,9H). 17 I-15 [([4-[(1E)-1-(2S,11S)-2- 1760.4 (400 MHz, CDCl₃) δ 8.71 (s,1H), 7.63 (d, [[(3S,4R)-1-carbamoyl-4-[(4-[1- J = 8.1 Hz, 2H), 7.55 (d,J = 8.1 Hz, 2H), 7.35 [2-([[(2S,4R)-1-[(2S)-2-[(1- (d, J = 7.8 Hz, 2H),7.26 (d, J = 7.7 Hz, 2H), fluorocyclopropyl)formamido]- 7.16 (d, J = 7.8Hz, 2H), 7.12-6.92 (m, 6H), 3,3-dimethylbutanoyl]-4- 6.91 (d, J = 1.6Hz, 1H), 6.81 (d, J = 9.5 Hz, hydroxypyrrolidin-2- 1H), 6.14 (s, 1H),5.95 (s, 1H), 5.76 (dd, J = yl]formamido]methyl)-5-(4- 12.5, 5.0 Hz,2H), 5.68 (dd, J = 12.4, 5.0 methyl-1,3-thiazol-5- Hz, 2H), 5.18 (dd, J= 8.7, 3.9 Hz, 1H), 4.97 yl)phenoxy]-3,6,9,12,15- (s, 1H), 4.71-4.54 (m,4H), 4.54-4.38 (m, pentaoxaoctadecan-18- 4H), 4.20 (ddt, J = 15.9, 10.0,5.4 Hz, 2H), yl]phenyl)methoxy]pentan-3- 4.06-3.84 (m, 4H), 3.83-3.71(m, 2H), 3.69- yl]carbamoyl]-12-oxo-1- 3.66 (m, 3H), 3.65-3.58 (m, 10H),3.57-3.51 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m,3H), 3.49-3.26 (m, 5H), 3.13 (d, J = 7.5 4(13),5,7-trien-11- Hz, 1H),2.64 (t, J = 7.6 Hz, 2H), 2.62-2.56 yl]carbamoyl]prop-1-en-2- (m, 3H),2.54 (s, 3H), 2.37 (td, J = 10.6, 8.3, yl]phenyl]difluoromethyl([(2,2-4.7 Hz, 2H), 2.19-2.02 (m, 4H), 1.86-1.72 dimethylpropanoyl)oxy]methoxy)(m, 4H), 1.42-1.27 (m, 5H), 1.24-1.06 (m, phosphoryl)oxy]methyl 2,2-21H), 0.98 (s, 9H). dimethylpropanoate 18 I-16[([4-[(1E)-1-[[(2S,11S)-2- 1716.5 (400 MHz, CDCl₃) δ 8.70 (s, 1H),7.67-7.59 [[(3S,4R)-1-carbamoyl-4-[(4-[1- (m, 2H), 7.55 (d, J = 8.2 Hz,2H), 7.35 (d, J = [2-([[(2S,4R)-1-[(2S)-2-[(1- 7.3 Hz, 2H), 7.26 (d, J =7.9 Hz, 2H), 7.15 fluorocyclopropyl)formamido]- (d, J = 7.8 Hz, 2H),7.13-7.01 (m, 4H), 7.01- 3,3-dimethylbutanoyl]-4- 6.89 (m, 3H), 6.81 (d,J = 9.4 Hz, 1H), 6.13 hydroxypyrrolidin-2- (d, J = 1.7 Hz, 1H), 5.95 (s,1H), 5.76 (ddd, yl]formamido]methyl)-5-(4- J = 12.5, 5.0, 0.9 Hz, 2H),5.68 (dd, J = 12.4, methyl-1,3-thiazol-5- 5.0 Hz, 2H), 5.18 (dd, J =8.6, 4.0 Hz, 1H), yl)phenoxy]-3,6,9,12- 4.96 (s, 1H), 4.67 (t, J = 7.9Hz, 1H), 4.64- tetraoxapentadecan-15- 4.54 (m, 3H), 4.53-4.39 (m, 4H),4.20 (tdd, J = yl]phenyl)methoxy]pentan-3- 10.1, 8.0, 4.3 Hz, 2H),4.05-3.85 (m, 4H), yl]carbamoyl]-12-oxo-1- 3.83-3.71 (m, 2H), 3.75-3.59(m, 9H), 3.62- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-3.53 (m, 3H), 3.44 (t, J = 6.4 Hz, 2H), 3.41- 4(13),5,7-trien-11- 3.28(m, 3H), 3.19-3.07 (m, 1H), 2.63 (t, J = yl]carbamoyl]prop-1-en-2- 7.6Hz, 2H), 2.62-2.55 (m, 3H), 2.54 (s, 3H),yl]phenyl]difluoromethyl([(2,2- 2.37 (ddd, J = 12.8, 8.0, 4.5 Hz, 2H),2.19- dimethylpropanoyl)oxy]methoxy) 1.87 (m, 6H), 1.90-1.74 (m, 3H),1.43-1.26 phosphoryl)oxy]methyl 2,2- (m, 4H), 1.24-1.06 (m, 21H), 0.98(s, 9H). dimethylpropanoate 19 I-17 [([4-[(1E)-1-[[(2S,11S)-2- 1672.7(400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.62 (d, J =[[(3S,4R)-1-carbamoyl-4-[(4-[3- 8.1 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H),7.41- [2-(2-[2-[2-([[(2S,4R)-1-[(2S)-2- 7.31 (m, 2H), 7.25 (d, J = 7.7Hz, 2H), 7.15 [(1- (d, J = 7.8 Hz, 2H), 7.12-7.00 (m, 4H), 7.01-fluorocyclopropyl)formamido]- 6.93 (m, 2H), 6.89 (d, J = 1.7 Hz, 1H),6.83 3,3-dimethylbutanoyl]-4- (d, J = 9.4 Hz, 1H), 6.14 (s, 1H), 5.98(s, hydroxypyrrolidin-2- 1H), 5.72-5.58 (m, 4H), 5.17 (dd, J = 8.2, 4.4yl]formamido]methyl)-5-(4- Hz, 1H), 5.05 (s, 1H), 4.66 (t, J = 7.9 Hz,methyl-1,3-thiazol-5- 1H), 4.65-4.53 (m, 3H), 4.54-4.38 (m, 4H), 4.yl)phenoxy]ethoxy]ethoxy)ethoxy] 19 (tq, J = 10.5, 5.3 Hz, 2H),3.97-3.87 (m, propyl]phenyl)methoxy]pentan- 4H), 3.85-3.51 (m, 10H),3.44 (t, J = 6.4 Hz, 3-yl]carbamoyl]-12-oxo-1- 2H), 3.34-3.22 (m, 3H),3.12 (d, J = 7.6 Hz, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 1H), 2.70-2.48 (m, 8H), 2.44-2.26 (m, 3H),4(13),5,7-trien-11- 2.13-2.02 (m, 4H), 1.99-1.72 (m, 4H), 1.52-yl]carbamoyl]prop-1-en-2- 1.39 (m, 4H), 1.24-1.05 (m, 21H), 0.97 (s,9H). yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 20 I-18[([4-[(1E)-1-[[(2S,11S)-2- 1629 (400 MHz, CDCl₃) δ 7.62 (d, J = 8.2 Hz,2H), [[(3S,4R)-1-carbamoyl-4-([4-[3- 7.55 (d, J = 8.2 Hz, 2H), 7.34 (td,J = 6.8, (2-[2-[2-([[(2S,4R)-1-[(2S)-2-[(1- 5.8, 2.4 Hz, 2H), 7.26 (d, J= 7.6 Hz, 2H), fluorocyclopropyl)formamido]- 7.15 (d, J = 7.8 Hz, 2H),7.12-6.94 (m, 6H), 3,3-dimethylbutanoyl]-4- 6.91 (d, J = 1.6 Hz, 1H),6.85 (d, J = 9.4 Hz, hydroxypyrrolidin-2- 1H), 6.19-6.10 (m, 1H), 6.00(s, 1H), 5.76 (ddd, yl]formamido]methyl)-5-(4- J = 12.5, 5.0, 1.4 Hz,2H), 5.68 (dd, J = methyl-1,3-thiazol-5- 12.4, 5.0 Hz, 2H), 5.17 (dd, J= 8.2, 4.5 Hz, yl)phenoxy]ethoxy]ethoxy)propyl] 1H), 5.08 (s, 1H),4.73-4.54 (m, 5H), 4.55-4.38 phenyl]methoxy)pentan-3- (m, 4H), 4.30-4.10(m, 2H), 4.04-3.88 (m, yl]carbamoyl]-12-oxo-1- 5H), 3.83-3.55 (m, 4H),3.46 (t, J = 6.5 Hz, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 2H), 3.41-3.26 (m, 3H), 3.12 (d, J = 7.8 Hz,4(13),5,7-trien-11- 1H), 2.70-2.59 (m, 2H), 2.60-2.55 (m, 3H),yl]carbamoyl]prop-1-en-2- 2.53 (s, 3H), 2.45-2.27 (m, 3H), 2.20-1.99yl]phenyl]difluoromethyl([(2,2- (m, 5H), 2.00-1.72 (m, 4H), 1.42-1.25(m, 4H), dimethylpropanoyl)oxy]methoxy) 1.24-1.03 (m, 21H), 0.97 (s,9H). phosphoryl)oxy]methyl 2,2- dimethylpropanoate 21 I-19[([4-[(1E)-1-[[(2S,11S)-2- 1585.2 (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.62(d, J = [[(3S,4R)-1-Carbamoyl-4-[[4-(3- 8.1 Hz, 2H), 7.55 (d, J = 8.1Hz, 2H), 7.35 [2-[2-([[(2S,4R)-1-[(2S)-2-[(1- (t, J = 6.4 Hz, 2H), 7.24(d, J = 7.7 Hz, 2H), fluorocyclopropyl)formamido]- 7.14 (d, J = 7.7 Hz,2H), 7.11-7.01 (m, 5H), 3,3-dimethylbutanoyl]-4- 6.98 (d, J = 7.7 Hz,1H), 6.92 (s, 1H), 6.87 hydroxypyrrolidin-2- (d, J = 9.5 Hz, 1H), 6.16(s, 1H), 6.03 (s, 1H), yl]formamido]methyl)-5-(4- 5.76 (dd, J = 12.5,5.0 Hz, 2H), 5.68 (dd, J = methyl-1,3-thiazol-5- 12.4, 5.1 Hz, 2H),5.25-5.03 (m, 2H), 4.72- yl)phenoxy]ethoxy]propyl)phenyl] 4.60 (m, 4H),4.53-4.37 (m, 4H), 4.20 (h, J = methoxy]pentan-3- 6.4, 5.9 Hz, 2H), 4.00(d, J = 10.4 Hz, 1H), yl]carbamoyl]-12-oxo-1- 3.94-3.78 (m, 3H),3.70-3.50 (m, 4H), 3.32- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 3.20 (m, 3H), 3.18-3.06 (m, 1H), 2.67 (t, J =4(13),5,7-trien-11- 7.5 Hz, 2H), 2.55 (d, J = 12.6 Hz, 6H), 2.43-yl]carbamoyl]prop-1-en-2- 2.25 (m, 3H), 2.19-1.98 (m, 5H), 1.95-1.86yl]phenyl]difluoromethyl([(2,2- (m, 3H), 1.82 (d, J = 10.4 Hz, 1H),1.39-1.27 dimethylpropanoyl)oxy]methoxy) (m, 3H), 1.24-1.03 (m, 21H),0.95 (s, 9H). phosphoryl)oxy]methyl 2,2- dimethylpropanoate 22 I-20[([4-[(1E)-1-[[(2S,11S)-2- 1540.9 (400 MHz, CDCl₃) δ 8.69 (s, 1H),7.66-7.58 [[(3S,4R)-1-carbamoyl-4-[(4-[3- (m, 2H), 7.54 (d, J = 8.2 Hz,2H), 7.36-7.29 [2-([[(2S,4R)-1-[(2S)-2-[(1- (m, 2H), 7.28 (s, 1H),7.25-7.13 (m, 3H), fluorocyclopropyl)formamido]- 7.12-6.99 (m, 5H), 6.96(dd, J = 7.7, 1.6 Hz, 3,3-dimethylbutanoyl]-4- 1H), 6.90-6.80 (m, 2H),6.15 (d, J = 1.5 Hz, hydroxypyrrolidin-2- 1H), 5.96 (s, 1H), 5.80-5.71(m, 2H), 5.67 yl]formamido]methyl)-5-(4- (ddd, J = 12.4, 5.0, 1.6 Hz,2H), 5.19 (dd, methyl-1,3-thiazol-5- J = 8.8, 3.8 Hz, 1H), 5.04 (s, 1H),4.72 (t, J = yl)phenoxy]propyl]phenyl) 7.7 Hz, 1H), 4.58 (dd, J = 16.1,10.3 Hz, 3H), methoxy]pentan-3-yl]carbamoyl]-12- 4.53-4.34 (m, 4H),4.08-3.89 (m, 4H), 3.62 oxo-1- (dt, J = 10.3, 5.1 Hz, 2H), 3.42-3.23 (m,4H), azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 3.17-3.04(m, 1H), 2.80 (t, J = 7.4 Hz, 2H), 4(13),5,7-trien-11- 2.63-2.54 (m,3H), 2.52 (s, 3H), 2.47 (dd, J = yl]carbamoyl]prop-1-en-2- 7.5, 5.0 Hz,1H), 2.37 (d, J = 12.9 Hz, 1H), yl]phenyl]difluoromethyl([(2,2-2.20-1.89 (m, 8H), 1.80 (tt, J = 13.4, 6.4 Hz,dimethylpropanoyl)oxy]methoxy) 1H), 1.40-1.28 (m, 3H), 1.24 -1.03 (m,21H), phosphoryl)oxy]methyl 2,2- 0.94 (s, 9H). dimethylpropanoate 23I-21 [([4-[(1E)-1-[[(2S,11S)-2- 1508.4 (400 MHz, CDCl₃) δ 8.70 (s, 1H),7.75 (t, [[(3S,4R)-1-carbamoyl-4-([4-[4- J = 6.2 Hz, 1H), 7.63 (d, J =8.1 Hz, 2H), 7.54 ([[(2S)-1-[(2S,4S)-4-hydroxy-2- (d, J = 8.2 Hz, 2H),7.45-7.32 (m, 4H), 7.26 ([[4-(4-methyl-1,3-thiazol-5- (d, J = 7.9 Hz,2H), 7.20-7.00 (m, 6H), 6.86 yl)phenyl]methyl]carbamoyl) (dd, J = 15.9,7.7 Hz, 2H), 6.11 (d, J = 1.6 Hz, pyrrolidin-1-yl]-3,3-dimethyl-1- 1H),5.76 (ddd, J = 12.4, 5.0, 3.2 Hz, 2H), oxobutan-2- 5.68 (ddd, J = 12.3,5.0, 1.5 Hz, 2H), 5.21 yl]carbamoyl]methoxy)butyl] (dd, J = 9.7, 2.8 Hz,1H), 5.06 (s, 1H), 4.73 phenyl]methoxy)pentan-3- (d, J = 9.0 Hz, 1H),4.68-4.53 (m, 4H), 4.48 yl]carbamoyl]-12-oxo-1- (s, 1H), 4.44-4.29 (m,2H), 4.03-3.81 (m, 5H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 3.59 (dt, J = 10.7, 6.1 Hz, 1H), 3.50 (t, J =4(13),5,7-trien-11- 6.1 Hz, 2H), 3.44-3.26 (m, 3H), 3.13 (d, J =yl]carbamoyl]prop-1-en-2- 17.7 Hz, 1H), 2.66-2.49 (m, 8H), 2.43-2.30yl]phenyl]difluoromethyl([(2,2- (m, 2H), 2.25-2.13 (m, 1H), 2.14-1.99(m, 3H), dimethylpropanoyl)oxy]methoxy) 2.02-1.86 (m, 2H), 1.80 (dq, J =13.9, 6.8 phosphoryl)oxy]methyl 2,2- Hz, 1H), 1.73-1.56 (m, 5H),1.24-1.01 (m, dimethylpropanoate 21H), 0.96 (s, 9H). 24 I-22[([4-[(1E)-1-[(2S,11S)-2- [(M/2 + 1)]⁺ = (400 MHz, CDCl₃) δ 8.79 (s,1H), 7.74 (t, [[(3S,4R)-1-carbamoyl-4-([4-[3-  748.9 J = 5.9 Hz, 1H),7.62 (d, J = 8.2 Hz, 2H), 7.54 ([[(2S)-1-[(2S,4S)-4-hydroxy-2- (d, J =8.2 Hz, 2H), 7.36-7.22 (m, 4H), 7.15- ([[4-(4-methyl-1,3-thiazol-5- 7.08(m, 3H), 7.07-7.01 (m, 3H), 6.97 (d, J = yl)phenyl]methyl]carbamoyl) 6.1Hz, 1H), 6.87 (d, J = 9.4 Hz, 1H), 6.13 pyrrolidin-1-yl]-3,3-dimethyl-1-(s, 1H), 5.86 (s, 1H), 5.76 (ddd, J = 12.4, 5.0, oxobutan-2- 3.4 Hz,2H), 5.68 (ddd, J = 12.4, 5.0, 2.1 yl]carbamoyl]methoxy)propyl] Hz, 2H),5.20 (dd, J = 9.9, 2.7 Hz, 1H), 5.11 phenyl]methoxy)pentan-3- (s, 1H),4.73 (d, J = 9.0 Hz, 1H), 4.61-4.55 yl]carbamoyl]-12-oxo-1- (m, 4H),4.52-4.38 (m, 2H), 4.31 (dd, J = 15.0, azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca- 5.0 Hz, 1H), 4.03-3.81 (m, 6H), 3.59 (dd,4(13),5,7-trien-11- J = 6.4, 4.5 Hz, 1H), 3.55-3.48 (m, 3H), 3.46-yl]carbamoyl]prop-1-en-2- 3.26 (m, 3H), 3.12 (d, J = 7.4 Hz, 1H), 2.65yl]phenyl]difluoromethyl([(2,2- (t, J = 7.7 Hz, 2H), 2.59-2.53 (m, 3H),2.52 dimethylpropanoyl)oxy]methoxy) (s, 3H), 2.33 (d, J = 14.5 Hz, 2H),2.24-2.04 phosphoryl)oxy]methyl 2,2- (m, 3H), 2.01 (d, J = 7.9 Hz, 1H),1.90-1.81 dimethylpropanoate (m, 4H), 1.79 (dq, J = 13.6, 7.0 Hz, 1H),1.24-1.02 (m, 21H), 0.97 (s, 9H). 25 I-23 [([4-[(1E)-1-[[(2S,11S)-2-1568.9 (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.62 (d,[[(3S,4R)-1-carbamoyl-4-[(4-[5- J = 8.1 Hz, 2H), 7.54 (d, J = 8.2 Hz,2H), 7.32 [2-([[(2S,4R)-1-[(2S)-2-[(1- (dd, J = 11.9, 6.9 Hz, 2H), 7.26(s, 1H), 7.16 fluorocyclopropyl)formamido]- (d, J = 7.8 Hz, 2H), 7.06(m, 4H), 6.99-6.91 3,3-dimethylbutanoyl]-4- (m, 2H), 6.87-6.80 (m, 2H),6.14 (d, J = 1.6 hydroxypyrrolidin-2- Hz, 1H), 5.93 (s, 1H), 5.76 (ddd,J = 12.5, yl]formamido]methyl)-5-(4- 5.0, 1.6 Hz, 2H), 5.68 (dd, J =12.3, 5.0 Hz, methyl-1,3-thiazol-5- 2H), 5.18 (dd, J = 8.7, 3.9 Hz, 1H),5.00 (s, yl)phenoxy]pentyl]phenyl) 1H), 4.73 (t, J = 7.7 Hz, 1H),4.64-4.33 (m, methoxy]pentan-3-yl]carbamoyl]-12- 7H), 3.98-3.76 (m, 4H),3.69-3.55 (m, 2H), oxo-1- 3.41-3.26 (m, 3H), 3.12 (d, J = 7.6 Hz, 1H),azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2.62 (t, J = 7.3Hz, 2H), 2.60-2.54 (m, 3H), 4(13),5,7-trien-11- 2.53-2.44 (m, 4H),2.42-2.31 (m, 1H), 2.19- yl]carbamoyl]prop-1-en-2- 2.00 (m, 4H), 1.95(dd, J = 8.9, 5.4 Hz, 1H), yl]phenyl]difluoromethyl([(2,2- 1.85-1.76 (m,3H), 1.70 (p, J = 7.4 Hz, 2H), dimethylpropanoyl)oxy]methoxy) 1.57-1.46(m, 3H), 1.40-1.27 (m, 4H), 1.24- phosphoryl)oxy]methyl 2,2- 1.15 (m,21H), 1.09 (dd, J = 15.4, 4.3 Hz, dimethylpropanoate. 1H), 0.96 (s, 9H).26 I-24 [([4-[(1E)-1-[[(2S,11S)-2- 1368.8 (400 MHz, CDCl₃) δ 9.14 (d, J= 7.3 Hz, [[(3S,4R)-1-carbamoyl-4-([4-[3- 1H), 7.68-7.51 (m, 4H),7.28-7.19 (m, 2H), (2-[3-[1-(2,6-dioxopiperidin-3- 7.19-6.80 (m, 9H),6.74-6.65 (m, 1H), 6.19 (d, yl)-3-methyl-2-oxo-1,3- J = 8.8 Hz, 1H),6.01 (d, J = 8.0 Hz, 1H), benzodiazol-4- 5.72-5.51 (m, 4H), 5.35-5.03(m, 3H), 4.71- yl]propoxy]ethoxy)propyl]phenyl] 4.49 (m, 2H), 4.38 (dd,J = 11.8, 4.0 Hz, 1H), methoxy)pentan-3- 3.95 (s, 1H), 3.72-3.43 (m,12H), 3.41-3.26 yl]carbamoyl]-12-oxo-1- (m, 1H), 3.22-2.97 (m, 4H),2.94-2.61 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-5H), 2.58-2.46 (m, 3H), 2.38 (d, J = 13.4 Hz, 4(13),5,7-trien-11- 2H),2.14-2.03 (m, 4H), 2.01-1.73 (m, 6H), yl]carbamoyl]prop-1-en-2- 1.24 (s,18H), 1.18 (s, 3H). yl]phenyl]difluoromethyl([(2,2-dimethylpropanoyl)oxy]methoxy) phosphoryl)oxy]methyl 2,2-dimethylpropanoate 27 I-25 [([4-[(1E)-1-[[(2S,11S)-2- 1438.2 (400 MHz,CDCl₃) δ 7.63 (d, J = 8.1 Hz, 2H), [[(3S,4R)-1-carbamoyl-4-[(4-[3- 7.55(d, J = 8.2 Hz, 2H), 7.27-7.01 (m, 6H),[(6-[3-[3-methyl-1-(1-methyl-2,6- 6.95-6.84 (m, 3H), 6.75 (dd, J = 42.7,8.7 dioxopiperidin-3-yl)-2-oxo-1,3- Hz, 2H), 6.12 (d, J = 1.6 Hz, 1H),5.93 (s, benzodiazol-5- 1H), 5.76 (dd, J = 12.5, 5.0 Hz, 2H), 5.68 (dd,yl]propoxy]hexyl)oxy]propyl] J = 12.4, 5.0 Hz, 2H), 5.18 (dt, J = 8.6,4.6 phenyl)methoxy]pentan-3- Hz, 2H), 4.93 (s, 1H), 4.60 (d, J = 11.5Hz, yl]carbamoyl]-12-oxo-1- 2H), 4.43 (d, J = 11.6 Hz, 1H), 4.04-3.91(m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1H), 3.61(dd, J = 6.5, 4.0 Hz, 1H), 3.46-3.32 4(13),5,7-trien-11- (m, 13H), 3.25(s, 3H), 3.18-2.97 (m, 2H), yl]carbamoyl]prop-1-en-2- 2.90-2.59 (m, 6H),2.57-2.45 (m, 3H), 2.42- yl]phenyl]difluoromethyl([(2,2- 1.74 (m, 12H),1.68-1.54 (m, 4H), 1.41-1.27 dimethylpropanoyl)oxy]methoxy) (m, 4H),1.24-1.03 (m, 22H). phosphoryl)oxy]methyl 2,2- dimethylpropanoate 28I-26 [([4-[(1E)-1-[[(2S,11S)-2- [(M + 23)]⁺ = (400 MHz, CDCl₃) δ 8.69(s, 1H), 7.77-7.42 [[(3S,4R)-1-carbamoyl-4-[(4-[4- 1576.3 (m, 4H),7.45-6.69 (m, 12H), 6.09 (d, J = 6.0 [2-([[(2S,4R)-1-[(2S)-2-[(1- Hz,2H), 5.71-5.58 (m, 4H), 5.16 (s, 2H), fluorocyclopropyl)formamido]-4.75-4.24 (m, 8H), 3.93-3.78 (m, 4H), 3.70- 3,3-dimethylbutanoyl]-4-3.01 (m, 7H), 2.83-2.44 (m, 8H), 2.43-2.24 hydroxypyrrolidin-2- (m, 3H),2.24-2.01 (m, 4H), 2.00-1.89 (m, yl]formamido]methyl)-5-(4- 3H),1.23-1.13 (m, 28H), 0.91-0.83 (m, methyl-1,3-thiazol-5- 10H).yl)phenoxy]butyl]phenyl) methoxy]pentan-3-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 29 I-27[([4-[(1E)-1-[[(2S,11S)-2- 1614.9 (400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.63(d, J = [[(3S,4R)-1-Carbamoyl-4-[[4-(1- 8.2 Hz, 2H), 7.55 (d, J = 8.2Hz, 2H), 7.45 [[(2S)-1-[(2S,4R)-4-hydroxy-2- (d, J = 6.3 Hz, 1H),7.42-7.30 (m, 4H), 7.28- ([[4-(4-methyl-1,3-thiazol-5- 7.20 (m, 3H),7.19 (d, J = 7.7 Hz, 2H), 7.16- yl)phenyl]methyl]carbamoyl) 7.06 (m,3H), 7.02-6.97 (m, 1H), 6.91 (d, J = pyrrolidin-1-yl]-3,3-dimethyl-1-9.4 Hz, 1H), 6.15 (s, 1H), 6.08 (s, 1H), 5.76 oxobutan-2-yl]carbamoyl]-(dd, J = 12.5, 5.0 Hz, 2H), 5.68 (dd, J = 12.4,2,5,8,11-tetraoxatridecan-13- 5.0 Hz, 2H), 5.23-5.12 (m, 2H), 4.71 (t, J= yl)phenyl]methoxy]pentan-3- 8.0 Hz, 1H), 4.65-4.55 (m, 2H), 4.52-4.45yl]carbamoyl]-12-oxo-1- (m, 3H), 4.44-4.31 (m, 2H), 4.10-4.01 (m,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1H), 3.98-3.88(m, 3H), 3.67-3.58 (m, 15H), 4(13),5,7-trien-11- 3.33-3.22 (m, 3H), 3.12(d, J = 7.1 Hz, 1H), yl]carbamoyl]prop-1-en-2- 2.85 (t, J = 7.0 Hz, 2H),2.57 (s, 3H), 2.55- yl]phenyl]difluoromethyl([(2,2- 2.46 (m, 4H), 2.37(d, J = 13.6 Hz, 1H), 2.18- dimethylpropanoyl)oxy]methoxy) 2.03 (m, 4H),1.93 (s, 1H), 1.78 (d, J = 10.6 phosphoryl)oxy]methyl 2,2- Hz, 1H),1.24-1.05 (m, 23H), 0.97 (s, 9H). dimethylpropanoate 30 I-28[([4-[(1E)-1-[[(2S,11S)-2- (400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.72-7.47[[(3S,4R)-1-carbamoyl-4-[[4-(6- 1508.0 (m, 4H), 7.43-7.30 (m, 5H), 7.27(d, J = 14.7 [[(2S)-1-[(2S,4R)-4-hydroxy-2- Hz, 2H), 7.18-7.02 (m, 5H),6.97 (d, J = 6.0 ([[4-(4-methyl-1,3-thiazol-5- Hz, 1H), 6.87 (d, J = 9.4Hz, 1H), 6.33-5.93 yl)phenyl]methyl]carbamoyl) (m, 3H), 5.72-5.59 (m,4H), 5.26-5.05 (m, pyrrolidin-1-yl]-3,3-dimethyl-1- 2H), 4.82-4.26 (m,8H), 4.14-3.89 (m, 2H), oxobutan-2- 3.73-3.44 (m, 3H), 3.34 (t, J = 11.2Hz, 3H), yl]carbamoyl]hexyl)phenyl] 3.11 (d, J = 7.4 Hz, 1H), 2.67-2.44(m, 9H), methoxy]pentan-3-yl]carbamoyl]-12- 2.34 (s, 1H), 2.25-1.68 (m,10H), 1.24-1.03 oxo-1- (m, 27H), 0.94 (s, 9H).azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 31 I-29[([4-[(1E)-1-[[(2S,11S)-2- 1352.8 (400 MHz, CDCl₃) δ 8.87 (d, J = 7.1Hz, 1H), [[(3S,4R)-1-carbamoyl-4-(4-[3- 7.62 (d, J = 8.3 Hz, 2H), 7.56(d, J = 8.2 Hz, ([5-[1-(2,6-dioxopiperidin-3-yl)- 2H), 7.26 (t, J = 7.4Hz, 2H), 7.18-7.01 (m, 3-methyl-2-oxo-1,3-benzodiazol- 5H), 7.01-6.92(m, 2H), 6.92-6.80 (m, 2H), 4- 6.68 (d, J = 7.7 Hz, 1H), 6.16 (d, J =10.4 Hz, yl]pentyl]oxy)propyl]phenyl] 1H), 5.94 (s, 1H), 5.76 (dd, J =12.5, 5.0 Hz, methoxy)pentan-3-yl]carbamoyl]-12- 2H), 5.68 (dd, J =12.4, 5.0 Hz, 2H), 5.19- oxo-1- 5.13 (m, 2H), 5.05 (d, J = 8.3 Hz, 1H),4.59 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (dd, J =11.5, 8.4 Hz, 2H), 4.43 (dd, J = 11.9, 4(13),5,7-trien-11- 2.0 Hz, 1H),3.98 (s, 1H), 3.70-3.54 (m, 4H), yl]carbamoyl]prop-1-en-2- 3.33 (d, J =6.2 Hz, 1H), 3.25 (d, J = 8.3 Hz, yl]phenyl]difluoromethyl([(2,2- 1H),3.13 (d, J = 7.5 Hz, 1H), 3.08-2.81 (m, dimethylpropanoyl)oxy]methoxy)4H), 2.79-2.68 (m, 1H), 2.67-2.60 (m, 2H), phosphoryl)oxy]methyl 2,2-2.58-2.48 (m, 3H), 2.37 (s, 1H), 2.23-2.02 dimethylpropanoate (m, 4H),2.02-1.76 (m, 5H), 1.66-1.54 (m, 4H), 1.52 (q, J = 7.7 Hz, 3H), 1.34 (t,J = 7.2 Hz, 2H), 1.24 (s, 18H), 1.21-1.12 (m, 4H). 32 I-30[([4-[(1E)-1-(2S,11S)-2- 1526.5 (400 MHz, CDCl₃) δ 8.68 (s, 1H), 7.61(d, J = [[(3S,4R)-1-carbamoyl-4-[[4-(2- 8.2 Hz, 2H), 7.55 (s, 2H), 7.49(t, J = 5.8 [2-[2-([[(2S)-1-[(2S,4R)-4- Hz, 1H), 7.46-7.34 (m, 4H),7.31-7.22 (m, hydroxy-2-([[4-(4-methyl-1,3- 3H), 7.18 (d, J = 7.7 Hz,2H), 7.14-7.03 (m, thiazol-5- 4H), 6.95 (d, J = 9.4 Hz, 1H), 6.15 (s,2H), yl)phenyl]methyl]carbamoyl) 5.75 (ddd, J = 12.5, 5.0, 1.4 Hz, 2H),5.67 pyrrolidin-1-yl]-3,3-dimethyl-1- (dd, J = 12.4, 5.0 Hz, 2H), 5.29(s, 1H), 5.18 oxobutan-2-yl]carbamoyl]methoxy)ethoxy] (dd, J = 8.8, 4.1Hz, 1H), 4.69 (t, J = 7.8 Hz, ethoxy]ethyl)phenyl]methoxy]pentan- 1H),4.65-4.45 (m, 5H), 4.45-4.27 (m, 2H), 3-yl]carbamoyl]-12-oxo-1-4.18-3.88 (m, 4H), 3.71 (d, J = 1.2 Hz, 1H),azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 3.67-3.51 (m,8H), 3.41-3.23 (m, 3H), 3.10 4(13),5,7-trien-11- (d, J = 7.4 Hz, 1H),2.83 (t, J = 6.8 Hz, 2H), yl]carbamoyl]prop-1-en-2- 2.66-2.57 (m, 3H),2.56-2.50 (m, 3H), 2.49- yl]phenyl]difluoromethyl([(2,2- 2.38 (m, 1H),2.39-2.29 (m, 1H), 2.14-2.04 dimethylpropanoyl)oxy]methoxy) (m, 4H),1.91 (d, J = 8.2 Hz, 1H), 1.74 (q, phosphoryl)oxy]methyl 2,2- J = 8.6,6.5 Hz, 1H), 1.23 (s, 18H), 1.23-1.05 dimethylpropanoate (m, 7H), 0.96(s, 9H). 33 I-31 [([4-[(1E)-1-[[(2S,11S)-2- 1526.5 (400 MHz, CDCl₃) δ8.68 (s, 1H), 7.68-7.44 [[(3S,4R)-1-carbamoyl-4-[(4-[2- (m, 5H),7.32-7.16 (m, 6H), 7.13-6.90 (m, [2-([[(2S)-1-[(2S,4R)-4-hydroxy- 5H),6.14 (d, J = 14.2 Hz, 2H), 5.83-5.60 (m, 2-([[4-(4-methyl-1,3-thiazol-5-4H), 5.18 (d, J = 8.3 Hz, 2H), 4.79-4.27 (m, yl)phenyl]methyl]carbamoyl)8H), 4.11-3.49 (m, 13H), 3.43-3.03 (m, 4H),pyrrolidin-1-yl]-3,3-dimethyl-1- 2.88 (d, J = 7.4 Hz, 2H), 2.66-2.51 (m,7H), oxobutan-2- 2.39-1.67 (m, 9H), 1.24-1.03 (m, 22H), 0.98yl]carbamoyl]methoxy)ethoxy] (s, 9H). ethyl]phenyl)methoxy]pentan-3-yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 34 I-32[([4-[(1E)-1-[[(2S,11S)-2- [(M + 23)]⁺ = (400 MHz, CDCl₃) δ 8.68 (s,1H), 7.79-7.43 [[(3S,4R)-1-carbamoyl-4-[[4-(1- 1649.8 (m, 5H), 7.26-7.18(m, 4H), 7.14 (d, J = 7.6 [[(2S)-1-[(2S,4R)-4-hydroxy-2- Hz, 2H), 7.07(d, J = 7.2 Hz, 2H), 7.06-6.98 ([[4-(4-methyl-1,3-thiazol-5- (m, 4H),6.90 (d, J = 9.5 Hz, 1H), 6.13 (d, J = yl)phenyl]methyl]carbamoyl) 11.8Hz, 2H), 5.71-5.58 (m, 5H), 5.18 (d, J =pyrrolidin-1-yl]-3,3-dimethyl-1- 5.6 Hz, 2H), 4.70 (t, J = 7.9 Hz, 1H),4.64- oxobutan-2-yl]carbamoyl]- 4.47 (m, 6H), 4.45-4.30 (m, 3H),3.98-3.83 2,5,8,11-tetraoxatetradecan-14- (m, 5H), 3.59-3.43 (m, 6H),3.38-3.20 (m, yl)phenyl]methoxy]pentan-3- 6H), 3.11 (d, J = 7.5 Hz, 1H),2.73-2.40 (m, yl]carbamoyl]-12-oxo-1- 9H), 2.35 (d, J = 13.1 Hz, 2H),2.19-1.70 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-12H), 1.23-1.02 (m, 21 H), 0.96 (s, 9H). 4(13),5,7-trien-11-yl]carbamoyl]prop-1-en-2- yl]phenyl]difluoromethyl([(2,2-dimethylpropanoyl)oxy]methoxy) phosphoryl)oxy]methyl 2,2-dimethylpropanoate 35 I-33 [([4-[(1E)-1-[[(2S,11S)-2- 1584.9 (400 MHz,CDCl₃) δ 8.77 (s, 1H), 7.67-7.54 [[(3S,4R)-1-Carbamoyl-4-[[4-(3- (m,4H), 7.37-7.23 (m, 5H), 7.18-6.88 (m, [2-[2-([[(2S)-1-[(2S,4R)-4- 7H),6.10 (d, J = 40.0 Hz, 2H), 5.72-5.63 (m, hydroxy-2-([[4-(4-methyl-1,3-4H), 5.16 (d, J = 6.5 Hz, 2H), 4.73 (t, J = 7.8 thiazol-5- Hz, 1H),4.66-4.48 (m, 5H), 4.46-4.33 (m, yl)phenyl]methyl]carbamoyl) 2H), 4.07(t, J = 10.2 Hz, 1H), 4.02-3.92 (m, pyrrolidin-1-yl]-3,3-dimethyl-1-3H), 3.71-3.56 (m, 10H), 3.47-3.31 (m, 5H), oxobutan-2- 3.13 (d, J = 7.4Hz, 1H), 2.65 (t, J = 7.6 Hz, yl]carbamoyl]methoxy)ethoxy] 2H),2.56-2.43 (m, 7H), 2.38 (d, J = 13.5 Hz, ethoxy]propyl)phenyl]methoxy]1H), 2.18-2.04 (m, 4H), 1.86-1.70 (m, 5H),pentan-3-yl]carbamoyl]-12-oxo-1- 1.25-1.02 (m, 24H), 0.97 (s, 9H).azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 36 I-34[([4-[(1E)-1-[[(2S,11S)-2- 1510.9 (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.63(d, J = [[(3S,4R)-1-Carbamoyl-4-([4-[4- 8.1 Hz, 2H), 7.58-7.47 (m, 3H),7.39-7.30 ([[(2S)-1-[(2S,4R)-4-hydroxy-2- (m, 4H), 7.28 (d, J = 5.0 Hz,2H), 7.21-7.13 ([[4-(4-methyl-1,3-thiazol-5- (m, 3H), 7.07-6.94 (m, 3H),6.92 (dd, J = yl)phenyl]methyl]carbamoyl) 15.7, 7.7 Hz, 2H), 6.06 (d, J= 8.7 Hz, 2H), pyrrolidin-1-yl]-3,3-dimethyl-1- 5.80-5.65 (m, 4H),5.23-5.10 (m, 2H), 4.72 oxobutan-2- (t, J = 8.0 Hz, 1H), 4.65-4.50 (m,5H), 4.38 yl]carbamoyl]methoxy)butyl] (dd, J = 13.8, 5.6 Hz, 2H), 4.06(d, J = 11.2 phenyl]methoxy)pentan-3- Hz, 1H), 3.95 (s, 1H), 3.83 (q, J= 15.3 Hz, yl]carbamoyl]-12-oxo-1- 2H), 3.69-3.54 (m, 2H), 3.47 (d, J =8.0 Hz, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2H),3.32-3.21 (m, 3H), 3.13 (d, J = 7.4 Hz, 4(13),5,7-trien-11- 1H),2.64-2.42 (m, 10H), 2.07-1.83 (m, 6H), yl]carbamoyl]prop-1-en-2-1.79-1.57 (m, 5H), 1.24-1.03 (m, 21H), 0.97yl]phenyl]difluoromethyl([(2,2- (s, 9H). dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 37 I-35[([4-[(1E)-1-[[(2S,11S)-2- 1497 (400 MHz, CDCl₃) δ 8.77 (s, 1H), 7.62(d, [[(3S,4R)-1-Carbamoyl-4-([4-[3- J = 8.3 Hz, 2H), 7.57-7.48 (m, 3H),7.35 (s, ([[(2S)-1-[(2S,4R)-4-hydroxy-2- 4H), 7.30-7.21 (m, 4H),7.17-7.00 (m, 6H), ([[4-(4-methyl-1,3-thiazol-5- 6.91 (d, J = 9.5 Hz,1H), 6.07 (d, J = 65.0 Hz, yl)phenyl]methyl]carbamoyl) 2H), 5.80-5.63(m, 4H), 5.33-5.10 (m, 2H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.72 (t, J= 8.0 Hz, 1H), 4.64-4.49 (m, 5H), oxobutan-2- 4.45-4.30 (m, 2H),3.99-3.88 (m, 4H), 3.83 yl]carbamoyl]methoxy)propyl] (d, J = 6.3 Hz,1H), 3.66 (dd, J = 11.1, 3.8 phenyl]methoxy)pentan-3- Hz, 1H), 3.57 (s,1H), 3.52-3.42 (m, 2H), yl]carbamoyl]-12-oxo-1- 3.33 (s, 1H), 3.11 (d, J= 7.2 Hz, 1H), 2.66 (t, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- J = 7.6 Hz, 2H), 2.58-2.55 (m, 3H), 2.43 (s,4(13),5,7-trien-11- 1H), 2.36 (d, J = 12.6 Hz, 2H), 2.20-2.10 (m,yl]carbamoyl]prop-1-en-2- 4H), 2.02 (q, J = 7.6 Hz, 1H), 1.95-1.86 (m,yl]phenyl]difluoromethyl([(2,2- 3H), 1.76 (s, 2H), 1.24-1.03 (m, 21H),0.98 dimethylpropanoyl)oxy]methoxy) (s, 9H), 0.85 (d, J = 8.1 Hz, 1H).phosphoryl)oxy]methyl 2,2- dimethylpropanoate 38 I-36[([4-[(1E)-1-[[(2S,11S)-2- 1352.8 (400 MHz, CDCl₃) δ 9.02 (d, J = 7.9Hz, 1H), [[(3S,4R)-1-carbamoyl-4-([4-[3- 7.58-7.43 (m, 4H), 7.25 (dd, J= 7.8, 3.5 Hz, ([5-[1-(2,6-dioxopiperidin-3-yl)- 2H), 7.16-6.96 (m, 6H),6.89 (d, J = 8.2 Hz, 3-methyl-2-oxo-1,3-benzodiazol- 2H), 6.85 (s, 1H),6.73 (d, J = 7.9 Hz, 1H), 5- 6.28-6.00 (m, 2H), 5.76 (dd, J = 12.5, 5.0Hz, yl]pentyl]oxy)propyl]phenyl] 2H), 5.68 (dd, J = 12.4, 5.0 Hz, 2H),5.33 (s, methoxy)pentan-3-yl]carbamoyl]-12- 1H), 5.25-5.09 (m, 2H), 4.59(dd, J = 11.5, oxo-1- 4.7 Hz, 2H), 4.42 (d, J = 11.6 Hz, 1H), 3.98azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (s, 1H), 3.59(s, 1H), 3.39-3.20 (m, 10H), 4(13),5,7-trien-11- 3.12 (d, J = 7.5 Hz,1H), 2.95-2.77 (m, 2H), yl]carbamoyl]prop-1-en-2- 2.76-2.62 (m, 5H),2.58 (s, 3H), 2.38 (s, 1H), yl]phenyl]difluoromethyl([(2,2- 2.14-2.02(m, 4H), 1.95 (s, 1H), 1.85-1.73 dimethylpropanoyl)oxy]methoxy) (m, 3H),1.62-1.50 (m, 4H), 1.43 (q, J = 8.4 phosphoryl)oxy]methyl 2,2- Hz, 2H),1.24 (s, 18H), 1.21-1.16 (m, 3H). dimethylpropanoate 39 I-37[([4-(1E)-1-[(2S,11S)-2- 1539.9 (400 MHz, CDCl₃) δ 8.75 (s, 1H), 7.62(d, J = [[(3S,4R)-1-Carbamoyl-4-[(4-[3- 8.1 Hz, 2H), 7.54 (d, J = 8.2Hz, 2H), 7.44 [2-([[(2S)-1-[(2S,4R)-4-hydroxy- (t, J = 5.9 Hz, 1H),7.38-7.31 (m, 4H), 7.28 2-([[4-(4-methyl-1,3-thiazol-5- (s, 2H), 7.16(d, J = 7.7 Hz, 2H), 7.12-6.98 ( yl)phenyl]methyl]carbamoyl) m, 4H),6.92 (d, J = 9.3 Hz, 1H), 6.15 (s, 1H), pyrrolidin-1-yl]-3,3-dimethyl-1-6.04 (s, 1H), 5.76 (ddd, J = 12.5, 5.0, 2.2 oxobutan-2- Hz, 2H), 5.68(dd, J = 12.4, 5.0 Hz, 2H), 5.20 yl]carbamoyl]methoxy)ethoxy] (t, J =6.4 Hz, 1H), 5.12 (s, 1H), 4.71 (t, J = propyl]phenyl)methoxy]pentan-3-7.9 Hz, 1H), 4.61 (d, J = 12.4 Hz, 2H), 4.56 yl]carbamoyl]-12-oxo-1- (d,J = 6.4 Hz, 1H), 4.54-4.46 (m, 3H), 4.41 azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca- (d, J = 11.6 Hz, 1H), 4.33 (dd, J = 15.0,4(13),5,7-trien-11- 5.3 Hz, 1H), 4.10-4.02 (m, 1H), 3.97-3.86 (m,yl]carbamoyl]prop-1-en-2- 3H), 3.69-3.55 (m, 7H), 3.46 (q, J = 6.5, 5.2yl]phenyl]difluoromethyl([(2,2- Hz, 2H), 3.38-3.28 (m, 3H), 3.12 (d, J =7.5 dimethylpropanoyl)oxy]methoxy) Hz, 1H), 2.65 (t, J = 7.6 Hz, 2H),2.57 (s, 3H), phosphoryl)oxy]methyl 2,2- 2.52-2.46 (m, 4H), 2.37 (d, J =12.8 Hz, dimethylpropanoate 1H), 2.10-1.92 (m, 4H), 1.88-1.81 (m, 3H),1.80-1.68 (m, 1H), 1.24-1.03 (m, 21H), 0.97 (s, 9H). 40 I-38[([4-[(1E)-1-[[(2S,11S)-2- 1352.8 (400 MHz, CDCl₃) δ 9.24 (d, J = 8.4Hz, 1H), [[(3S,4R)-1-carbamoyl-4-[[4-(5- 7.62 (d, J = 8.3 Hz, 2H), 7.56(d, J = 8.2 Hz, [3-[1-(2,6-dioxopiperidin-3-yl)-3- 2H), 7.28-7.20 (m,3H), 7.17-7.00 (m, 6H), methyl-2-oxo-1,3-benzodiazol-4- 6.96 (q, J = 7.8Hz, 1H), 6.87 (q, J = 8.3, 7.4 yl]propoxy]pentyl)phenyl]methoxy] Hz,2H), 6.70 (d, J = 7.8 Hz, 1H), 6.25-6.17 pentan-3-yl]carbamoyl]-12- (m,1H), 6.17-6.03 (m, 1H), 5.76 (dd, J = oxo-1- 12.5, 5.1 Hz, 2H), 5.67(dd, J = 12.4, 5.0 Hz, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 2H), 5.34-5.08 (m, 3H), 4.61 (dd, J = 10.3,4(13),5,7-trien-11- 5.9 Hz, 1H), 4.49 (dd, J = 17.8, 11.6 Hz, 1H),yl]carbamoyl]prop-1-en-2- 4.36 (d, J = 11.6 Hz, 1H), 3.96 (d, J = 10.3yl]phenyl]difluoromethyl([(2,2- Hz, 1H), 3.66-3.52 (m, 4H), 3.48-3.26(m, dimethylpropanoyl)oxy]methoxy) 6H), 3.25-3.18 (m, 1H), 3.11 (d, J =7.5 Hz, phosphoryl)oxy]methyl 2,2- 1H), 2.95 (td, J = 14.4, 11.6, 7.2Hz, 2H), dimethylpropanoate 2.90-2.69 (m, 3H), 2.60 (d, J = 7.0 Hz, 1H),2.37 (d, J = 11.9 Hz, 1H), 2.23-2.02 (m, 4H), 2.01-1.71 (m, 4H),1.61-1.46 (m, 5H), 1.38- 1.27 (m, 3H), 1.24 (s, 18H), 1.21-1.12 (m, 4H).41 I-39 [([4-[(1E)-1-[[(2S,11S)-2- 1382.9 (400 MHz, CDCl₃) δ 7.80-7.44(m, 4H), [[(3S,4R)-1-carbamoyl-4-([4-[3- 7.33-6.76 (m, 10H), 6.64 (d, J= 7.7 Hz, 1H), (2-[3-[3-methyl-1-(1-methyl-2,6- 6.15 (s, 1H), 5.98 (s,1H), 5.71-5.58 (m, 4H), dioxopiperidin-3-yl)-2-oxo-1,3- 5.19 (dq, J =13.9, 7.2, 6.7 Hz, 2H), 4.98 (d, benzodiazol-4- J = 12.6 Hz, 1H), 4.58(d, J = 11.0 Hz, 2H), yl]propoxy]ethoxy)propyl]phenyl] 4.42 (d, J = 11.6Hz, 1H), 3.96 (s, 1H), 3.78- methoxy)pentan-3- 3.41 (m, 12H), 3.43-3.17(m, 6H), 3.17-2.91 yl]carbamoyl]-12-oxo-1- (m, 4H), 2.92-2.51 (m, 7H),2.47-1.68 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-12H), 1.27-1.03 (m, 21H). 4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl((2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 42 I-40[([4-[(1E)-1-[[(2S,11S)-2- 1383 (400 MHz, CDCl₃) δ 9.17 (d, J = 7.5 Hz,1H), [[(3S,4R)-1-carbamoyl-4-([4-[3- 7.72-7.50 (m, 4H), 7.28-7.19 (m,2H), 7.19- (3-[3-[1-(2,6-dioxopiperidin-3- 7.10 (m, 2H), 7.10-6.82 (m,7H), 6.74-6.67 yl)-3-methyl-2-oxo-1,3- (m, 1H), 6.19 (d, J = 9.0 Hz,1H), 6.01 (s, benzodiazol-4- 1H), 5.72-5.55 (m, 4H), 5.31-5.04 (m, 3H),yl]propoxy]propoxy)propyl] 4.68-4.34 (m, 3H), 3.97 (s, 1H), 3.66 (s,3H), phenyl]methoxy)pentan-3- 3.62-3.48 (m, 7H), 3.46-2.62 (m, 13H),2.58 yl]carbamoyl]-12-oxo-1- (s, 3H), 2.38 (d, J = 13.6 Hz, 1H),2.27-2.01 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m,4H), 1.89-1.51 (m, 8H), 1.24 (s, 18H), 4(13),5,7-trien-11- 1.18 (s, 3H).yl]carbamoyl]prop-1-en-2- yl]phenyl]difluoromethyl([(2,2-dimethylpropanoyl)oxy]methoxy) phosphoryl)oxy]methyl 2,2-dimethylpropanoate 43 I-41 [([4-[(1E)-1-[[(2S,11S)-2- 1396.9 (400 MHz,CDCl₃) δ 8.98 (d, J = 8.9 Hz, 1H), [[(3S,4R)-1-carbamoyl-4-([4-[3-7.67-7.49 (m, 4H), 7.35-7.13 (m, 4H), 7.11-(4-[3-[1-(2,6-dioxopiperidin-3- 6.65 (m, 9H), 6.22-6.01 (m, 3H),5.72-5.41 yl)-3-methyl-2-oxo-1,3- (m, 4H), 5.32-5.02 (m, 3H), 4.66-4.35(m, benzodiazol-4- 4H), 3.68-3.55 (m, 6H), 3.52-2.54 (m, 21H),yl]propoxy]butoxy)propyl]phenyl] 2.46-1.80 (m, 12H), 1.24-1.03 (m, 21H).methoxy)pentan-3- yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca- 4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 44 I-42[([4-[(1E)-1-[[(2S,11S)-2- 1412.9 (400 MHz, CDCl₃) δ 9.07 (d, J = 8.1Hz, 1H), [[(3S,4R)-1-Carbamoyl-4-[(4-[3- 7.61-7.41 (m, 4H), 7.21 (d, J =9.3 Hz, 2H), [2-(2-[3-[1-(2,6-dioxopiperidin-3- 7.16-7.00 (m, 5H),6.92-6.84 (m, 3H), 6.70 yl)-3-methyl-2-oxo-1,3-benzodiazol-4- (d, J =7.5 Hz, 1H), 6.27-5.94 (m, 2H), 5.76 yl]propoxy]ethoxy)ethoxy]propyl](dd, J = 12.5, 5.0 Hz, 2H), 5.68 (dd, J = 12.3, phenyl)methoxy]pentan-3-5.0 Hz, 2H), 5.17-5.01 (m, 3H), 4.56 (d, J = yl]carbamoyl]-12-oxo-1- 6.9Hz, 2H), 4.39 (d, J = 10.4 Hz, 1H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 3.97 (s, 1H), 3.73-3.58 (m, 10H), 3.53-3.49 (m,4(13),5,7-trien-11- 3H), 3.48 (d, J = 4.8 Hz, 2H), 3.32 (d, J = 8.4yl]carbamoyl]prop-1-en-2- Hz, 2H), 3.21-3.07 (m, 2H), 3.01 (d, J =yl]phenyl]difluoromethyl([(2,2- 7.6 Hz, 2H), 2.95-2.72 (m, 3H), 2.65 (t,J = 7.8 dimethylpropanoyl)oxy]methoxy) Hz, 2H), 2.61-2.52 (m, 3H), 2.38(s, 1H), phosphoryl)oxy]methyl 2,2- 2.16-1.91 (m, 5H), 1.89-1.53 (m,7H), 1.24-1.03 dimethylpropanoate (m, 21H). 45 I-43[([4-[(1E)-1-[[(2S,11S)-2- 1410.9 (400 MHz, CDCl₃) δ 9.10 (d, J = 10.1Hz, [[(3S,4R)-1-carbamoyl-4-[(4-[3- 1H), 7.72-7.40 (m, 4H), 7.28-7.19(m, 2H), [(5-[3-[1-(2,6-dioxopiperidin-3- 6.99-6.72 (m, 9H), 6.69 (d, J= 7.7 Hz, 1H), yl)-3-methyl-2-oxo-1,3- 6.18 (d, J = 10.2 Hz, 1H), 6.06(s, 1H), 5.76 benzodiazol-4- (dd, J = 12.5, 5.0 Hz, 2H), 5.68 (dd, J =12.4, yl]propoxy]pentypoxy]propyl] 5.0 Hz, 2H), 5.37-5.03 (m, 3H),4.71-4.49 phenyl)methoxy]pentan-3- (m, 2H), 4.40 (dd, J = 11.7, 3.7 Hz,1H), 3.97 yl]carbamoyl]-12-oxo-1- (s, 1H), 3.67 (s, 3H), 3.63-3.51 (m,1H), azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 3.52-3.25(m, 10H), 3.24-3.07 (m, 2H), 3.06- 4(13),5,7-trien-11- 2.70 (m, 5H),2.65 (t, J = 7.7 Hz, 2H), 2.58 yl]carbamoyl]prop-1-en-2- (s, 3H), 2.37(d, J = 13.5 Hz, 1H), 2.25-2.01 yl]phenyl]difluoromethyl([(2,2- (m, 5H),1.99-1.72 (m, 6H), 1.62-1.51 (m, dimethylpropanoyl)oxy]methoxy) 3H),1.48 (s, 2H), 1.24 (s, 18H), 1.19 (s, 3H). phosphoryl)oxy]methyl 2,2-dimethylpropanoate 46 I-44 [([4-[(1E)-1-[[(2S,11S)-2- 1424.9 (400 MHz,CDCl₃) δ 8.98 (d, J = 8.6 Hz, 1H), [[(3S,4R)-1-carbamoyl-4-[(4-[3- 7.62(d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.3 Hz,[(6-[3-[1-(2,6-dioxopiperidin-3- 2H), 7.25-7.17 (m, 5H), 7.15-7.12 (m,5H), yl)-3-methyl-2-oxo-1,3- 7.11-6.93 (m, 5H), 6.93-6.79 (m, 2H), 6.69benzodiazol-4- (d, J = 7.7 Hz, 1H), 6.23-6.05 (m, 2H), 5.76yl]propoxy]hexyl)oxy]propyl] (dd, J = 12.5, 5.0 Hz, 2H), 5.68 (dd, J =12.4, phenyl)methoxy]pentan-3- 5.0 Hz, 2H), 5.41-5.05 (m, 3H), 4.68-4.50yl]carbamoyl]-12-oxo-1- (m, 2H), 4.41 (d, J = 11.5 Hz, 1H), 3.97 (s,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1H), 3.67 (s,3H), 3.58 (s, 1H), 3.44-3.35 (m, 4(13),5,7-trien-11- 7H), 3.30-3.18 (m,3H), 3.11 (d, J = 7.5 Hz, yl]carbamoyl]prop-1-en-2- 1H), 3.07-2.96 (m,2H), 2.95-2.69 (m, 3H), yl]phenyl]difluoromethyl([(2,2- 2.65 (t, J = 7.6Hz, 2H), 2.58 (s, 3H), 2.43- dimethylpropanoyl)oxy]methoxy) 2.01 (m,6H), 1.86-1.51 (m, 5H), 1.42-1.28 phosphoryl)oxy]methyl 2,2- (m, 4H),1.24-1.02 (m, 20H). dimethylpropanoate 47 I-45[([4-[(1E)-1-[[(2S,11S)-2- 1438.9 (400 MHz, CDCl₃) δ 9.00 (d, J = 8.7Hz, 1H), [[(3S,4R)-1-carbamoyl-4-[(4-[3- 7.62 (d, J = 8.1 Hz, 2H), 7.55(d, J = 8.2 Hz, [(7-[3-[1-(2,6-dioxopiperidin-3- 2H), 7.26 (dd, J = 7.8,3.9 Hz, 2H), 7.15 (dd, yl)-3-methyl-2-oxo-1,3- J = 7.7, 5.0 Hz, 2H),7.06-6.92 (m, 4H), 6.88- benzodiazol-5- 6.77 (m, 3H), 6.74 (d, J = 7.3Hz, 1H), 6.17 yl]propoxy]heptypoxy]propyl] (d, J = 6.2 Hz, 1H), 6.10 (s,1H), 5.76 (dd, J = phenyl)methoxy]pentan-3- 12.5, 5.0 Hz, 2H), 5.68 (dd,J = 12.3, 5.0 yl]carbamoyl]-12-oxo-1- Hz, 2H), 5.20-5.01 (m, 3H),4.66-4.51 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-3H), 4.42 (d, J = 11.6 Hz, 1H), 3.98 (s, 1H), 4(13),5,7-trien-11- 3.58(s, 2H), 3.42-3.18 (m, 14H), 3.12 (d, J = yl]carbamoyl]prop-1-en-2- 17.4Hz, 1H), 2.97-2.79 (m, 3H), 2.74-2.68 yl]phenyl]difluoromethyl([(2,2-(m, 3H), 2.65 (t, J = 7.7 Hz, 2H), 2.58 (s, 3H),dimethylpropanoyl)oxy]methoxy) 2.36 (s, 1H), 2.22 (s, 2H), 2.10 (s, 3H),1.87- phosphoryl)oxy]methyl 2,2- 1.54 (m, 6H), 1.39-1.28 (m, 6H),1.24-1.03 dimethylpropanoate (m, 21H). 48 I-46[([4-[(1E)-1-[[(2S,11S)-2- 1396.8 (400 MHz, CDCl₃) δ 8.87 (d, J = 6.5Hz, 1H), [[(3S,4R)-1-Carbamoyl-4-([4-[3- 7.69-7.52 (m, 4H), 7.12-6.93(m, 6H), 6.81- (4-[3-[1 -(2,6-dioxopiperidin-3- 6.51 (m, 4H), 6.11 (d, J= 7.5 Hz, 2H), 5.73- yl)-3-methyl-2-oxo-1,3- 5.43 (m, 4H), 5.21 (s, 3H),4.61 (s, 2H), 4.42 benzodiazol-5- (d, J = 11.6 Hz, 1H), 3.98 (s, 1H),3.60 (s, yl]propoxy]butoxy)propyl]phenyl] 1H), 3.55-3.18 (m, 15H), 3.13(d, J = 17.4 methoxy)pentan-3- Hz, 1H), 2.97-2.55 (m, 10H), 2.45-1.75(m, yl]carbamoyl]-12-oxo-1- 15H), 1.25-1.04 (m, 22H).azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 49 I-47[([4-[(1E)-1-[[(2S,11S)-2- 1411 (400 MHz, CDCl₃) δ 9.30 (d, J = 8.7 Hz,[[(3S,4R)-1-carbamoyl-4-[(4-[3- 1H), 7.73-7.46 (m, 4H), 7.24 (dd, J =7.8, 5.9 [(5-[3-[1-(2,6-dioxopiperidin-3- Hz, 2H), 7.18-6.99 (m, 6H),6.93-6.83 (m, yl)-3-methyl-2-oxo-1,3- 3H), 6.73 (dd, J = 7.9, 1.9 Hz,1H), 6.26-6.04 benzodiazol-5- (m, 2H), 5.72-5.61 (m, 4H), 5.45-5.09 (m,yl]propoxy]pentypoxy]propyl] 3H), 4.71-4.50 (m, 2H), 4.41 (d, J = 11.6Hz, phenyl)methoxy]pentan-3- 1H), 4.11-3.89 (m, J = 5.8 Hz, 2H), 3.56(d, yl]carbamoyl]-12-oxo-1- J = 8.5 Hz, 1H), 3.52-3.18 (m, 14H), 3.11(d, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- J = 17.5 Hz,1H), 2.95-2.78 (m, 2H), 2.78-2.60 4(13),5,7-trien-11- (m, 5H), 2.57-2.42(m, 3H), 2.36 (d, J = yl]carbamoyl]prop-1-en-2- 13.3 Hz, 1H), 2.24-2.03(m, 5H), 2.00-1.71 yl]phenyl]difluoromethyl([(2,2- (m, 6H), 1.63-1.50(m, 4H), 1.48 (tt, J = 8.8, dimethylpropanoyl)oxy]methoxy) 3.8 Hz, 1H),1.22-1.01 (m, 20H). phosphoryl)oxy]methyl 2,2- dimethylpropanoate 50I-48 [4-[(1E)-1-[[(2S,11S)-2-[[(3S,4R)- 1211.7 (400 MHz, D₂O) δ7.49-7.32 (m, 4H), 7.17- 1-carbamoyl-4-[(4-[3-[2-(2-[3-[3- 6.10 (m,11H), 4.99-4.75 (m, 2H), 4.24-4.03 methyl-1-(1-methyl-2,6- (m, 3H), 3.85(s, 3H), 3.65-2.75 (m, 16H), dioxopiperidin-3-yl)-2-oxo-1,3- 2.81-2.52(m, 4H), 2.52-1.29 (m, 20H), 0.97 benzodiazol-5- (s, 3H).yl]propoxy]ethoxy)acetamido] propyl]phenyl)methoxy]pentan-3-yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethylphosphonic acid 51 I-49([4-[(1E)-1-[[(2S,11S)-2- 1241.9 (400 MHz, D₂O) δ 7.58-7.45 (m, 4H),7.06- [[(3S,4R)-1-carbamoyl-4-[[4-[3- 6.74 (m, 10H), 6.21 (s, 1H), 5.36(s, 1H), [2-[2-(2-[3-[1-(2,6- 5.14-5.10 (m, 1H), 5.01-4.90 (m, 1H),4.47- dioxopiperidin-3-yl)-3-methyl-2- 4.36 (m, 1H), 4.29 (s, 2H), 3.89(s, 3H), 3.65- oxo-2,3-dihydro-1H-1,3- 3.47 (m, 6H), 3.46 (s, 2H),3.37-3.28 (m, benzodiazol-5- 2H), 3.17 (s, 3H), 3.12-3.02 (m, 2H), 2.98(s, yl]propoxy]ethoxy)ethoxy]acetamido] 1H), 2.71 (s, 3H), 2.51 (s, 3H),2.42-2.32 (m, propyl)phenyl]methoxy] 2H), 2.34-2.22 (m, 3H), 2.15 (s,2H), 2.04 (s, pentan-3-yl]carbamoyl]-12-oxo-1- 2H), 2.00-1.88 (m, 1H),1.86-1.58 (m, 2H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 1.60-1.49 (m, 3H), 1.20 (s, 1H), 1.08-1.044(13),5,7-trien-11- (m, 2H), 1.03-0.96 (m, 3H).yl]carbamoyl]prop-1-en-2- yl]phenyl]difluoromethyl) phosphonic acid 52I-50 [([4-[(1E)-1-[[(2S,11S)-2- 1353.9 (400 MHz, CDCl₃) δ 9.16 (dd, J =10.7, 5.5 [[(3S,4R)-1-carbamoyl-4-[[4-(5- Hz, 1H), 7.62 (d, J = 8.2 Hz,2H), 7.56 (d, J = [3-[1-(2,6-dioxopiperidin-3-yl)-3- 8.3 Hz, 2H), 7.24(d, J = 7.6 Hz, 2H), 7.14 methyl-2-oxo-1,3-benzodiazol-5- (dd, J = 7.8,3.2 Hz, 2H), 7.06-6.96 (m, 4H), yl]propoxy]pentyl)phenyl]methoxy] 6.86(d, J = 8.9 Hz, 3H), 6.75 (d, J = 7.9 Hz, pentan-3-yl]carbamoyl]-12-1H), 6.19 (d, J = 5.7 Hz, 1H), 6.08 (s, 1H), oxo-1- 5.76 (dd, J = 12.5,5.0 Hz, 2H), 5.68 (dd, J = azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 12.4, 5.0 Hz, 2H), 5.23 (d, J = 11.7 Hz, 2H),4(13),5,7-trien-11- 5.16 (s, 1H), 4.61 (s, 1H), 4.54 (dd, J = 11.5,yl]carbamoyl]prop-1-en-2- 4.5 Hz, 1H), 4.37 (dd, J = 11.5, 5.2 Hz, 1H),yl]phenyl]difluoromethyl([(2,2- 3.97 (s, 1H), 3.56 (s, 1H), 3.46-3.33(m, 8H), dimethylpropanoyl)oxy]methoxy) 3.30 (s, 2H), 3.12 (d, J = 7.3Hz, 1H), 2.85 phosphoryl)oxy]methyl 2,2- (d, J = 8.9 Hz, 2H), 2.80-2.64(m, 3H), 2.62- dimethylpropanoate 2.50 (m, 5H), 2.37 (d, J = 12.8 Hz,1H), 2.15- 2.02 (m, 6H), 1.99-1.83 (m, 3H), 1.60-1.46 (m, 4H), 1.41 (q,J = 7.6, 7.1 Hz, 2H), 1.24 (s, 18H), 1.19-1.09 (m, 3H). 53 I-51[([4-[(1E)-1-[[(2S,11S)-2- 1425 (400 MHz, CDCl₃) δ 8.95 (d, J = 8.3 Hz,1H), [[(3S,4R)-1-carbamoyl-4-[(4-[3- 7.74-7.50 (m, 4H), 7.30-7.23 (m,2H), 7.19- [(6-[3-[1-(2,6-dioxopiperidin-3- 6.95 (m, 6H), 6.94-6.80 (m,3H), 6.74 (dd, J = yl)-3-methyl-2-oxo-1,3- 8.0, 1.7 Hz, 1H), 6.17 (d, J= 6.5 Hz, 1H), benzodiazol-5- 5.99 (s, 1H), 5.76 (dd, J = 12.5, 5.0 Hz,2H), yl]propoxy]hexyl)oxy]propyl] 5.68 (dd, J = 12.4, 5.0 Hz, 2H),5.29-5.07 (m, phenyl)methoxy]pentan-3- 3H), 4.60 (td, J = 11.2, 10.3,5.0 Hz, 2H), yl]carbamoyl]-12-oxo-1- 4.42 (d, J = 11.6 Hz, 1H), 3.98 (t,J = 10.7 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- Hz,1H), 3.59 (t, J = 5.9 Hz, 1H), 3.49-3.21 4(13),5,7-trien-11- (m, 14H),3.12 (dt, J = 17.6, 4.6 Hz, 1H), yl]carbamoyl]prop-1-en-2- 2.96-2.61 (m,7H), 2.58 (s, 3H), 2.38 (d, J = yl]phenyl]difluoromethyl([(2,2- 13.8 Hz,1H), 2.27-2.02 (m, 5H), 1.86-1.52 dimethylpropanoyl)oxy]methoxy) (m,8H), 1.42-1.30 (m, 5H), 1.24-1.01 (m, phosphoryl)oxy]methyl 2,2- 21H).dimethylpropanoate 54 I-52 [([4-[(1E)-1-[[(2S,11S)-2- 1452.7 (400 MHz,CDCl₃) δ 8.93 (d, J = 8.6 Hz, [[(3S,4R)-1-carbamoyl-4-[(4-[3- 1H), 7.62(d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 [(8-[3-[1-(2,6-dioxopiperidin-3-Hz, 2H), 7.28-7.20 (m, 2H), 7.15 (dd, J = 7.9, yl)-3-methyl-2-oxo-1,3-2.8 Hz, 2H), 7.07-6.93 (m, 4H), 6.88-6.78 benzodiazol-5- (m, 3H), 6.74(d, J = 7.9 Hz, 1H), 6.17 (d, J = yl]propoxy]octypoxy]propyl] 4.9 Hz,1H), 6.11 (s, 1H), 5.76 (dd, J = phenyl)methoxy]pentan-3- 12.5, 5.0 Hz,2H), 5.68 (dd, J = 12.4, 5.0 Hz, yl]carbamoyl]-12-oxo-1- 2H), 5.23-5.03(m, 3H), 4.66-4.52 (m, 2H), azatricyclo[6.4.1.0]{circumflex over( )}[4,13]]trideca- 4.42 (d, J = 11.5 Hz, 1H), 3.95 (d, J = 8.1 Hz,4(13),5,7-trien-11- 1H), 3.59 (s, 1H), 3.48-3.20 (m, 14H), 3.12yl]carbamoyl]prop-1-en-2- (d, J = 7.2 Hz, 1H), 2.97-2.80 (m, 2H), 2.69-yl]phenyl]difluoromethyl([(2,2- 2.59 (m, 6H), 2.58 (s, 3H), 2.37 (d, J =13.4 dimethylpropanoyl)oxy]methoxy) Hz, 1H), 2.21 (d, J = 12.4 Hz, 1H),2.08-1.91 phosphoryl)oxy]methyl 2,2- (m, 3H), 1.87-1.70 (m, 6H),1.66-1.50 (m, dimethylpropanoate 4H), 1.35-1.27 (m, 8H), 1.24-1.01 (m,20H). 55 I-53 [([4-[(1E)-1-[[(2S,11S)-2- 1382.7 (400 MHz, CDCl₃) δ 9.02(d, J = 8.9 Hz, 1H), [[(3S,4R)-1-carbamoyl-4-([4-[3- 7.62 (d, J = 7.9Hz, 2H), 7.56 (d, J = 8.3 Hz, (3-[3-[1-(2,6-dioxopiperidin-3- 2H), 7.24(s, 2H), 7.16-6.92 (m, 6H), 6.88- yl)-3-methyl-2-oxo-1,3- 6.76 (m, 3H),6.73 (d, J = 7.9 Hz, 1H), 6.19 benzodiazol-5- (d, J = 11.9 Hz, 1H), 6.03(s, 1H), 5.76 (dd, yl]propoxy]propoxy)propyl] J = 12.5, 5.0 Hz, 2H),5.68 (dd, J = 12.4, 5.0 phenyl]methoxy)pentan-3- Hz, 2H), 5.20-5.01 (m,3H), 4.59 (d, J = 16.5 yl]carbamoyl]-12-oxo-1- Hz, 2H), 4.41 (d, J =11.5 Hz, 1H), 3.98 (s, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 1H), 3.65-5.51 (m, 5H), 3.49-3.21 (m, 10H),4(13),5,7-trien-11- 3.13 (d, J = 17.5 Hz, 1H), 2.86 (d, J = 8.9yl]carbamoyl]prop-1-en-2- Hz, 2H), 2.70-2.61 (m, 5H), 2.58 (s, 3H), 2.38yl]phenyl]difluoromethyl([(2,2- (s, 1H), 2.11 (s, 4H), 1.98-1.72 (m,8H), dimethylpropanoyl)oxy]methoxy) 1.27-1.03 (m, 21H).phosphoryl)oxy]methyl 2,2- dimethylpropanoate 56 I-55[([4-[(1E)-1-(2S,11S)-2- 1412.8 (400 MHz, CDCl₃) δ 9.07 (d, J = 8.9 Hz,1H), [[(3S,4R)-1-carbamoyl-4-[(4-[3- 7.62 (d, J = 8.1 Hz, 2H), 7.57 (d,J = 8.3 Hz, [2-(2-[3-[1-(2,6-dioxopiperidin-3- 2H), 7.23 (t, J = 7.9 Hz,2H), 7.09-6.61 (m, yl)-3-methyl-2-oxo-1,3- 6H), 6.88-6.75 (m, 3H), 6.73(d, J = 8.0 Hz, benzodiazol-5- 1H), 6.20 (d, J = 14.5 Hz, 1H), 6.08 (s,1H), yl]propoxy]ethoxy)ethoxy]propyl] 5.76 (dd, J = 12.5, 5.0 Hz, 2H),5.68 (dd, J = phenyl)methoxy]pentan-3- 12.4, 5.0 Hz, 2H), 5.20-5.02 (m,3H), 4.66- yl]carbamoyl]-12-oxo-1- 4.52 (m, 2H), 4.41 (d, J = 11.5 Hz,1H), 4.06 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (h, J= 6.1 Hz, 1H), 3.97 (s, 1H), 3.76-3.69 4(13),5,7-trien-11- (m, 4H),3.65-3.52 (m, 5H), 3.49-3.43 (m, yl]carbamoyl]prop-1-en-2- 4H),3.42-3.20 (m, 6H), 3.13 (d, J = 7.6 Hz, yl]phenyl]difluoromethyl([(2,2-1H), 2.86 (d, J = 6.9 Hz, 2H), 2.69-2.60 (m,dimethylpropanoyl)oxy]methoxy) 5H), 2.58 (s, 3H), 2.38 (s, 1H),2.17-2.03 (m, phosphoryl)oxy]methyl 2,2- 4H), 2.00-1.73 (m, 2H), 1.60(s, 1H), 1.45 (d, dimethylpropanoate J = 2.0 Hz, 1H), 1.28 (s, 2H),1.24-1.02 (m, 20H). 57 I-56 [4-[(1E)-1-[[(2S)-1-[(1R,2S,5S)-2- 1192.7(400 MHz, D₂O) δ 7.55 (d, J = 8.4 Hz, 2H),[[(3S,4R)-1-carbamoyl-4-[(4-[3- 7.47 (d, J = 8.2 Hz, 2H), 7.11 (d, J =7.7 Hz, [2(2-[3-[1-(2,6-dioxopiperidin-3- 2H), 6.97 (d, J = 7.8 Hz, 2H),6.90 (s, 1H), yl)-3-methyl-2-oxo-1,3- 6.82 (s, 2H), 6.19 (s, 1H), 5.18(d, J = 11.5 benzodiazol-5- Hz, 1H), 4.35-4.03 (m, 4H), 3.90 (s, 3H),yl]propoxy]ethoxy)acetamido] 3.84 (d, J = 11.4 Hz, 1H), 3.60-3.52 (m,5H), propyl]phenyl)methoxy]pentan-3- 3.49-3.44 (m, 1H), 3.40 (t, J = 6.4Hz, 2H), yl]carbamoyl]-3- 3.19 (d, J = 2.4 Hz, 3H), 3.10 (t, J = 6.9 Hz,azabicyclo[3.1.0]hexan-3-yl]-1- 2H), 2.84-2.67 (m, 2H), 2.57 (t, J = 7.4Hz, oxohexan-2-yl]carbamoyl]prop-1- 2H), 2.48 (d, J = 12.2 Hz, 1H), 2.40(t, J = en-2- 7.7 Hz, 2H), 2.35 (s, 3H), 2.20-2.17 (m, 2H),yl]phenyl]difluoromethylphosphonic 1.98 (s, 1H), 1.76 (t, J = 7.1 Hz,2H), 1.70- acid 1.61 (m, 6H), 1.56-1.42 (m, 2H), 1.31-1.13 (m, 4H), 1.03(d, J = 6.2 Hz, 3H), 0.75 (t, J = 7.0 Hz, 3H), 0.58-0.41 (m, 2H). 58I-57 [4-[(1E)-1-[[(2S)-1-[(1R,2S,5S)-2- 1235.8 (400 MHz, CD₃OD) δ 7.70(d, J = 8.2 Hz, [[(3S,4R)-1-carbamoyl-4-[[4-[3- 2H), 7.53 (d, J = 8.1Hz, 2H), 7.27 (d, J = 7.8 [2-[2-(2-[3-[1-(2,6- Hz, 2H), 7.15 (d, J = 7.7Hz, 2H), 7.07-6.93 dioxopiperidin-3-yl)-3-methyl-2- (m, 3H), 6.32 (s,1H), 5.31-5.30 (m, 1H), oxo-1,3-benzodiazol-5- 4.58-4.44 (m, 4H),4.15-4.13 (m, 1H), 3.99 yl]propoxy]ethoxy)ethoxy] (s, 2H), 3.91 (d, J =9.2 Hz, 1H), 3.77 (d, J = acetamido]propyl)phenyl]methoxy] 9.9 Hz, 1H),3.69-3.62 (m, 6H), 3.60-3.58 pentan-3-yl]carbamoyl]-3- (m, 2H),3.55-3.46 (m, 3H), 3.40 (s, 3H), azabicyclo[3.1.0]hexan-3-yl]-1-3.26-3.22 (m, 2H), 2.93-2.88 (m, 1H), 2.86-oxohexan-2-yl]carbamoyl]prop-1- 2.71 (m, 4H), 2.60 (t, J = 7.8 Hz, 2H),2.52- en-2- 2.49 (m, 3H), 2.34-2.23 (m, 2H), 2.15-2.11yl]phenyl]difluoromethylphosphonic (m, 2H), 1.96-1.84 (m, 3H), 1.79-1.73(m, acid 4H), 1.71-1.54 (m, 2H), 1.43-1.35 (m, 4H), 1.20-1.15 (m, 3H),0.96 (t, J = 7.0 Hz, 3H), 0.87 (d, J = 4.6 Hz, 1H), 0.67 (q, J = 7.8 Hz,1H). 59 I-58 [([4-[(1E)-1-[[(2S)-1-[(1R,2S,5S)- 1421.1 (400 MHz, CDCl₃)δ 9.69 (d, J = 8.0 Hz, 1H), 2-[[(3S,4R)-1-carbamoyl-4-[(4-[3- 7.60-7.55(m, 4H), 7.15-7.10 (m, 3H), 7.03 [2-(2-[3-[1-(2,6-dioxopiperidin-3- (d,J = 7.7 Hz, 1H), 6.92-6.83 (m, 2H), 6.85- yl)-3-methyl-2-oxo-1,3- 6.75(m, 2H), 6.69-6.65 (m, 1H), 6.51-6.47 benzodiazol-5- (m, 1H), 6.21 (d, J= 8.4 Hz, 1H), 5.81-5.72 yl]propoxy]ethoxy)acetamido] (m, 2H), 5.68-5.41(m, 2H), 5.31-5.12 (m, propyl]phenyl)methoxy]pentan-3- 1H), 4.79 (d, J =7.2 Hz, 1H), 4.56 (t, J = 12.2 yl]carbamoyl]-3- Hz, 1H), 4.30-4.27 (m,2H), 4.11-4.02 (m, azabicyclo[3.1.0]hexan-3-yl]-1- 3H), 3.98 (s, 1H),3.78 (d, J = 10.0 Hz, 1H), oxohexan-2-yl]carbamoyl]prop-1- 3.71 (s, 2H),3.63 (s, 2H), 3.54-3.46 (m, 3H), en-2- 3.35-3.28 (m, 5H), 2.88 (d, J =20.3 Hz, 2H), yl]phenyl]difluoromethyl([(2,2- 2.73-2.68 (m, 3H),2.63-2.55 (m, 4H), 2.48- dimethylpropanoyl)oxy]methoxy) 2.35 (m, 2H),2.21 (s, 1H), 2.10-1.89 (m, phosphoryl)oxy]methyl 2,2- 7H), 1.83 (d, J =7.3 Hz, 2H), 1.38-1.29 (m, dimethylpropanoate 4H), 1.24-1.20 (m, 22H),1.19-1.13 (m, 3H), 1.06 (d, J = 13.9 Hz, 1H), 0.91-0.86 (m, 3H), 0.67(s, 1H). 60 I-59 [([4-[(1E)-1-[[(2S)-1-[(1R,2S,5S)- 1463.9 (400 MHz,CDCl₃) δ 9.53 (d, J = 7.6 Hz, 1H), 2-[[(3S,4R)-1-carbamoyl-4-[[4-(3-7.60 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.2 Hz, [2-[2-(2-[3-[1-(2,6- 2H),7.23-7.08 (m, 4H), 7.05 (d, J = 7.7 Hz, dioxopiperidin-3-yl)-3-methyl-2-1H), 6.86-6.82 (m, 3H), 6.80-6.72 (m, 1H), oxo-1,3-benzodiazol-5- 6.66(d, J = 7.8 Hz, 1H), 6.32-6.30 (m, 1H), yl]propoxy]ethoxy)ethoxy] 6.18(d, J = 7.4 Hz, 1H), 5.80-5.71 (m, 2H), acetamido]propyl)phenyl]methoxy]5.68-5.55 (m, 2H), 5.51 (s, 1H), 5.23 (d, J = pentan-3-yl]carbamoyl]-3-12.2 Hz, 1H), 4.78 (d, J = 7.1 Hz, 1H), 4.54azabicyclo[3.1.0]hexan-3-yl]-1- (d, J = 11.7 Hz, 1H), 4.32-4.29 (m, 2H),4.13- oxohexan-2-yl]carbamoyl]prop-1- 3.91 (m, 5H), 3.78 (d, J = 9.9 Hz,1H), 3.69 en-2- (d, J = 6.3 Hz, 6H), 3.60-3.58 (m, 2H), 3.46-yl]phenyl]difluoromethyl([(2,2- 3.43 (m, 2H), 3.39-3.33 (m, 4H), 3.32(d, J = dimethylpropanoyl)oxy]methoxy) 7.1 Hz, 2H), 2.97-2.78 (m, 2H),2.78-2.52 phosphoryl)oxy]methyl 2,2- (m, 8H), 2.51-2.02 (m, 6H),1.87-1.45 (m, dimethylpropanoate 8H), 1.37-1.28 (m, 5H), 1.23-1.16 (m,23H). 61 I-60 [[([4-[(1E)-1-[[(2S,11S)-2- 1456.7 (400 MHz, CD₃OD) δ 7.69(d, J = 8.2 Hz, [[(3S,4R)-1-carbamoyl-4-[(4-[16- 2H), 7.62 (d, J = 8.3Hz, 2H), 7.22 (d, J = 7 .7 [1-(2,6-dioxopiperidin-3-yl)-3- Hz, 2H),7.12-7.05 (m, 3H), 7.04-6.97 (m, methyl-2-oxo-2,3-dihydro-1H- 4H), 6.95(d, J = 8.4 Hz, 1H), 6.41 (d, J = 1.5 1,3-benzodiazol-5-yl]-4,7,10,13-Hz, 1H), 5.81-5.66 (m, 4H), 5.31 (dd, J = tetraoxahexadecan-1- 12.5, 5.4Hz, 1H), 5.15 (dd, J = 11.0, 3.2 Hz, yl]phenyl)methoxy]pentan-3- 1H),4.65 (d, J = 9.8 Hz, 1H), 4.53-4.43 (m, yl]carbamoyl]-12-oxo-1- 2H),4.00 (s, 1H), 3.76-3.63 (m, 8H), 3.61- azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca- 3.53 (m, 5H), 3.51-3.44 (m, 5H), 3.40 (s,4(13),5,7-trien-11- 3H), 3.25-3.12 (m, 2H), 3.04-2.87 (m, 2H),yl]carbamoyl]prop-1-en-2- 2.77-2.67 (m, 4H), 2.65 (t, J = 7.6 Hz, 2H),yl]phenyl]difluoromethyl)([[(2,2- 2.55 (d, J = 1.4 Hz, 3H), 2.36-2.22(m, 4H), dimethylpropanoyl)oxy]methoxy]) 2.17-2.10 (m, 1H), 1.99 (d, J =7.0 Hz, 1H), phosphoryl]oxy]methyl 2,2- 1.86-1.72 (m, 4H), 1.68 (s, 1H),1.23-1.01 dimethylpropanoate (m, 21H). 62 I-61[[([4-[(1E)-1-[[(2S,11S)-2- 1337.7 (400 MHz, CD₃OD) δ 8.01 (d, J = 9.5Hz, [[(3S,4R)-1-carbamoyl-4-[[4-(3- 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.62(d, J = 8.3 [3-[1-(2,6-dioxopiperidin-3-yl)-3- Hz, 2H), 7.22 (d, J = 7.8Hz, 2H), 7.10-7.07 methyl-2-oxo-2,3-dihydro-1H- (m, 2H), 7.06-6.98 (m,6H), 6.41 (d, J = 4.1 1,3-benzodiazol-5- Hz, 1H), 5.75-5.34 (m, 4H),5.29-5.22 (m, yl]propanamido]propyl)phenyl] 1H), 5.18-5.16 (m, 1H), 4.66(d, J = 9.4 Hz, methoxy]pentan-3-yl]carbamoyl]- 1H), 4.57-4.44 (m, 2H),3.99 (s, 1H), 3.60- 12-oxo-1- 3.46 (m, 2H), 3.25-3.10 (m, 4H), 3.07-2.97azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m, 3H), 2.85(d, J = 15.5 Hz, 1H), 2.77-2.64 4(13),5,7-trien-11- (m, 2H), 2.58-2.51(m, 6H), 2.42-2.35 (m, yl]carbamoyl]prop-1-en-2- 2H), 2.34-2.19 (m, 4H),1.98 (d, J = 6.5 Hz, yl]phenyl]difluoromethyl)([[(2,2- 2H), 1.64-1.59(m, 3H), 1.23-1.15 (m, 22H). dimethylpropanoyl)oxy]methoxy])phosphoryl]oxy]methyl 2,2- dimethylpropanoate 63 I-62([4-[(1E)-1-[[(2S,11S)-2- 1109.5 (400 MHz, CD₃OD) δ 7.69 (d, J = 8.3 Hz,[[(3S,4R)-1-carbamoyl-4-[[4-(3- 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.20 (d,J = 7.8 [3-[1-(2,6-dioxopiperidin-3-yl)-3- Hz, 2H), 7.14 (d, J = 7.1 Hz,1H), 7.08-6.96 methyl-2-oxo-2,3-dihydro-1H- (m, 7H), 6.37 (s, 1H),5.28-5.10 (m, 4H), 1,3-benzodiazol-5- 4.50 (s, 3H), 4.02 (d, J = 11.6Hz, 1H), 3.63- yl]propanamido]propyl)phenyl] 3.58 (m, 1H), 3.53-3.46 (m,1H), 3.23-3.10 methoxy]pentan-3-yl]carbamoyl]- (m, 4H), 3.05-2.97 (m,3H), 2.86 (d, J = 10.9 12-oxo-1- Hz, 1H), 2.76 (d, J = 17.8 Hz, 1H),2.58-2.50 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m,6H), 2.33-1.88 (m, 9H), 1.72-1.57 (m, 4(13),5,7-trien-11- 3H), 1.30-1.21(m, 3H). yl]carbamoyl]prop-1-en-2- yl]phenyl]difluoromethyl) phosphonicacid 64 I-63 ([4-[(1E)-1-[[(2S,11S)-2- 1285.6 (400 MHz, D₂O) δ 7.62-7.41(m, 4H), 7.04- [[(3S,4R)-1-carbamoyl-4-[[4-(3- 6.67 (m, 10H), 6.21 (s,1H), 5.09 (s, 2H), [15-[1-(2,6-dioxopiperidin-3-yl)- 4.24-4.03 (m, 3H),3.85 (d, J = 7.8 Hz, 3H), 3-methyl-2-oxo-2,3-dihydro-1H- 3.62-3.33 (m,13H), 3.13-2.96 (m, 10H), 1,3-benzodiazol-5-yl]-3,6,9,12- 2.67-2.58 (m,3H), 2.56-2.26 (m, 8H), 2.26- tetraoxapentadecanamido]propyl) 1.42 (m,11H), 0.99-0.92 (m, 3H). phenyl]methoxy]pentan-3-yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl) phosphonic acid 65 I-64[[([4-(1E)-1-[[(2S,11S)-2- 1425.7 (400 MHz, CD₃OD) δ 7.95 (d, J = 8.7Hz, [[(3S,4R)-1-carbamoyl-4-[(4-[3- 1H), 7.70-7.54 (m, 4H), 7.22-7.15(m, 2H), [2-(2-[3-[1-(2,6-dioxopiperidin-3- 7.07 (d, J = 7.6 Hz, 3H),7.03-6.95 (m, 3H), yl)-3-methyl-2-oxo-2,3-dihydro- 6.95-6.88 (m, 1H),6.41-6.34 (m, 1H), 5.80- 1H-1,3 -benzodiazol-5- 5.52 (m, 3H), 5.34-5.25(m, 1H), 5.11-5.08 yl]propoxy]ethoxy)acetamido] (m, 1H), 4.63 (d, J =9.8 Hz, 1H), 4.52-4.40 propyl]phenyl)methoxy]pentan-3- (m, 2H) 4.02-3.87(m, 4H), 3.68-3.63 (m, yl]carbamoyl]-12-oxo-1- 2H), 3.62-3.60 (m, 2H),3.59-3.36 (m, 4H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 3.35 (s, 3H), 3.30-3.08 (m, 3H), 3.01-2.834(13),5,7-trien-11- (m, 2H), 2.83-2.67 (m, 4H), 2.58 (t, J = 7.8yl]carbamoyl]prop-1-en-2- Hz, 2H), 2.53-2.42 (m, 3H), 2.32-2.17 (m,yl]phenyl]difluoromethyl)([[(2,2- 4H), 2.16-2.05 (m, 1H), 1.99-1.74 (m,5H), dimethylpropanoyl)oxy]methoxy]) 1.67 (s, 1H), 1.32-1.23 (m, 4H),1.21 (s, phosphoryl]oxy]methyl 2,2- 18H). dimethylpropanoate 66 I-65([4-[(1E)-1-[[(2S,11S)-2- 1153.7 (400 MHz, CD₃OD) δ 7.69 (d, J = 8.2 Hz,[[(3S,4R)-1-carbamoyl-4-([4-[3- 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.23 (d,J = 7.8 (2-[3-[1-(2,6-dioxopiperidin-3- Hz, 2H), 7.13 (d, J = 7.9 Hz,3H), 7.09-6.96 yl)-3-methyl-2-oxo-2,3-dihydro- (m, 5H), 6.37 (d, J = 1.4Hz, 1H), 5.31 (dd, J = 1H-1,3-benzodiazol-5- 12.8, 5.3 Hz, 1H), 5.14 (d,J = 10.9 Hz, yl]propoxy]acetamido)propyl] 1H), 4.50 (s, 2H), 4.01 (d, J= 11.2 Hz, 1H), phenyl]methoxy)pentan-3- 3.93 (s, 2H), 3.64-3.57 (m,1H), 3.54 (t, J = yl]carbamoyl]-12-oxo-1- 6.4 Hz, 2H), 3.47 (d, J = 5.1Hz, 1H), 3.39 (s, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 3H), 3.27 (t, J = 7.0 Hz, 2H), 3.24-3.13 (m,4(13),5,7-trien-11- 2H), 2.97 (d, J = 11.6 Hz, 2H), 2.92-2.84 (m,yl]carbamoyl]prop-1-en-2- 1H), 2.79-2.68 (m, 3H), 2.61 (t, J = 7.7 Hz,yl]phenyl]difluoromethyl) 2H), 2.53-2.46 (m, 3H), 2.38-2.11 (m, 5H),phosphonic acid 2.03-1.93 (m, 3H), 1.87-1.78 (m, 2H), 1.69 (s, 1H),1.19-1.03 (m, 4H). 67 I-66 ([4-[(1E)-1-[[(2S,11S)-2- 1197.6 (400 MHz,CD₃OD) δ 7.69 (d, J = 8.2 Hz, [[(3S,4R)-1-carbamoyl-4-[(4-[3- 2H), 7.57(d, J = 8.1 Hz, 2H), 7.19 (dd, J = [2-(2-[3-[1-(2,6-dioxopiperidin-3-8.1, 1.9 Hz, 2H), 7.14-7.06 (m, 3H), 7.05-yl)-3-methyl-2-oxo-2,3-dihydro- 6.98 (m, 4H), 6.94 (d, J = 7.9 Hz, 1H),6.39- 1H-1,3-benzodiazol-5- 6.34 (m, 1H), 5.39-5.25 (m, 1H), 5.13 (dt, J= yl]propoxy]ethoxy)acetamido] 10.9, 3.6 Hz, 1H), 4.67-4.55 (m, 2H),4.47 propyl]phenyl)methoxy]pentan-3- (s, 2H), 4.01 (m, 3H), 3.73-3.62(m, 4H), yl]carbamoyl]-12-oxo-1- 3.60-3.39 (m, 4H), 3.37 (s, 3H),3.31-3.10 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m,4H), 3.00-2.87 (m, 2H), 2.86-2.67 (m, 4(13),5,7-trien-11- 4H), 2.59 (t,J = 7.8 Hz, 2H), 2.52 (d, J = 1.3 yl]carbamoyl]prop-1-en-2- Hz, 3H),2.37-2.09 (m, 3H), 2.04-1.85 (m, yl]phenyl]difluoromethyl) 3H),1.81-1.77 (m, 2H), 1.74-1.61 (m, 1H), phosphonic acid 1.29 (d, J = 9.5Hz, 1H), 1.22-1.12 (m, 3H). 68 I-67 [4-[(1E)-1-[(2S,11S)-24(3S,4R)-1255.7 (400 MHz, D₂O) δ 7.71-7.29 (m, 4H), 7.11-1-carbamoyl-4-[[4-(3-[2-[2-(2-[3- 6.15 (m, 11H), 4.99-4.85 (m, 2H),4.24-4.13 [3-methyl-1-(1-methyl-2,6- (m, 3H), 3.84 (s, 3H), 3.66-3.28(m, 9H), dioxopiperidin-3-yl)-2-oxo-1,3- 3.28-2.83 (m, 12H), 2.83-2.55(m, 4H), 2.53- benzodiazol-5- 1.40 (m, 19H), 0.97 (s, 3H).yl]propoxy]ethoxy)ethoxy]acetamido] propyl)phenyl]methoxy]pentan-3-yl]carbamoyl]-12-oxo-1- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethylphosphonic acid 69 I-68[[([4-[(1E)-1-[[(2S,11S)-2- 1381.7 (400 MHz, CD₃OD) δ 7.98 (d, J = 9.5Hz, [[(3S,4R)-1-carbamoyl-4-[[4-[3- 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.62(d, J = 8.3 (2-[3-[1-(2,6-dioxopiperidin-3- Hz, 2H), 7.24 (d, J = 7.8Hz, 2H), 7.18-7.08 yl)-3-methyl-2-oxo-2,3-dihydro- (m, 3H), 7.08-6.93(m, 5H), 6.41 (s, 1H), 1H-1,3 -benzodiazol-5- 5.75-5.63 (m, 4H), 5.31(dd, J = 12.7, 5.4 Hz, yl]propoxy]acetamido)propyl] 1H), 5.14 (d, J =10.6 Hz, 1H), 4.64 (d, J = phenyl]methoxy)pentan-3- 9.7 Hz, 1H),4.55-4.43 (m, 2H), 4.00 (s, 1H), yl]carbamoyl]-12-oxo-1- 3.91 (s, 2H),3.61-3.51 (m, 3H), 3.44 (d, J = azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 12.8 Hz, 1H), 3.38 (s, 3H), 3.27 (t, J = 7.14(13),5,7-trien-11- Hz, 2H), 3.24-3.10 (m, 2H), 3.00 (d, J = 16.7yl]carbamoyl]prop-1-en-2- Hz, 1H), 2.95-2.85 (m, 1H), 2.84-2.70 (m,yl]phenyl]difluoromethyl)([[2,2- 4H), 2.62 (t, J = 7.7 Hz, 2H), 2.55 (d,J = 1.3 dimethylpropanoyl)oxy]methoxy]) Hz, 3H), 2.26-2.19 (m, 4H),2.17-2.07 (m, phosphoryl]oxy]methyl 2,2- 1H), 1.98-1.84 (m, 3H), 1.82(p, J = 7.3 Hz, dimethylpropanoate 2H), 1.69 (q, J = 9.3, 5.0 Hz, 1H),1.24-1.13 (m, 20H). 70 I-69 [[([4-[(1E)-1-[[(2S,11S)-2- 1470.7 (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.53 [[(3S,4R)-1-carbamoyl-4-[[4-[3- (d, J =7.5 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 2-[2-(2-[3-[1-(2,6- 7.71-7.65 (m,3H), 7.60-7.52 (m, 2H), 7.20- dioxopiperidin-3-yl)-3-methyl-2- 7.11 (m,3H), 7.13-6.93 (m, 7H), 6.86 (d, J = oxo-2,3-dihydro-1H-1,3- 8.0 Hz,1H), 6.70 (s, 1H), 6.53 (s, 1H), 5.77- benzodiazol-5- 5.65 (m, 4H),5.33-5.28 (m, 1H), 5.13-5.05 yl]propoxy]ethoxy)ethoxy] (m, 1H), 4.48 (t,J = 8.3 Hz, 1H), 4.44-4.34 acetamido]propyl)phenyl]methoxy] (m, 2H),3.88(s, 2H), 3.79 (s, 1H), 3.63-3.54 pentan-3-yl]carbamoyl]-12-oxo-1- (m,6H), 3.52-3.48 (m, 2H), 3.47-3.36 (m, azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca- 4H), 3.31 (s, 3H), 3.23-3.01 (m, 4H), 2.86-2.834(13),5,7-trien-11- (m, 2H), 2.77-2.56 (m, 5H), 2.57-2.50 (m,yl]carbamoyl]prop-1-en-2- 3H), 2.17-1.93 (m, 5H), 1.86-1.64 (m, 5H),yl]phenyl]difluoromethyl)([[(2,2- 1.56 (s, 1H), 1.28-1.18 (m, 2H), 1.15(s, 18H), dimethylpropanoyl)oxy]methoxy]) 1.11 (s, 1H), 1.07 (s, 3H).phosphoryl]oxy]methyl 2,2- dimethylpropanoate 71 I-70[[([4-[(1E)-1-[[(2S,11S)-2- 1514.7 (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),8.54 [[(3S,4R)-1-carbamoyl-4-[[4-(3- (d, J = 7.5 Hz, 1H), 7.87 (d, J =9.2 Hz, 1H), [15-[1-(2,6-dioxopiperidin-3-yl)- 7.71 (d, J = 8.6 Hz, 3H),7.57 (d, J = 8.3 Hz, 3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]-3,6,9,12- 6.70 (s, 1H), 6.54 (s, 1H), 5.71-5.66(m, tetraoxapentadecanamido]propyl) 4H), 5.34-5.30 (m, 1H), 5.09 (d, J =8.9 Hz, phenyl]methoxy]pentan-3- 1H), 4.48-4.46 (m, 1H), 4.40 (s, 2H),3.87 (s, yl]carbamoyl]-12-oxo-1- 3H), 3.78 (d, J = 13.3 Hz, 1H),3.58-3.50 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-10H), 3.49-3.41 (m, 4H), 3.39 (t, J = 6.4 Hz, 4(13),5,7-trien-11- 3H),3.12-3.07 (m, 4H), 2.94-2.83 (m, 2H), yl]carbamoyl]prop-1-en-2-2.77-2.60 (m, 4H), 2.55-2.48 (m, 5H), 2.12-yl]phenyl]difluoromethyl)([[(2,2- 1.97 (m, 6H), 1.77-1.69 (m, 5H), 1.56(s, dimethylpropanoyl)oxy]methoxy]) 1H), 1.24 (s, 18H), 1.08 (s, 3H).phosphoryl]oxy]methyl 2,2- dimethylpropanoate 72 I-71[([4-[(1E)-1-[[(2S,11S)-2- 1494.9 (400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.62(d, J = [[(3S,4R)-1-Carbamoyl-4-[[4-(5- 8.1 Hz, 2H), 7.54 (d, J = 8.2Hz, 2H), 7.43- [(2S)-1-[(2S,4R)-4-hydroxy-2- 7.30 (m, 5H), 7.24 (d, J =7.7 Hz, 2H), 7.06- ([[4-(4-methyl-1,3-thiazol-5- 6.90 (m, 6H), 6.88 (d,J = 9.4 Hz, 1H), 6.38 yl)phenyl]methyl]carbamoyl) (d, J = 8.7 Hz, 1H),6.09 (d, J = 7.8 Hz, 2H), pyrrolidin-1-yl]-3,3-dimethyl-1- 5.82-5.61 (m,4H), 5.33-5.10 (m, 2H), 4.68 oxobutan-2- (t, J = 7.9 Hz, 1H), 4.64-4.44(m, 5H), 4.43- yl]carbamoyl]pentyl)phenyl] 4.28 (m, 2H), 4.06 (d, J =11.2 Hz, 1H), 3.95 methoxy]pentan-3-yl]carbamoyl]-12- (s, 1H), 3.60-3.50(m, 3H), 3.32-3.21 (m, 3H), oxo-1- 3.09 (d, J = 17.6 Hz, 1H), 2.63-2.27(m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 10H),2.21-1.68 (m, 8H), 1.56-1.40 (m, 4H), 4(13),5,7-trien-11- 1.23-1.04 (m,23H), 0.93 (s, 9H). yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2- dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2- dimethylpropanoate 73 I-80 diammonium[4-[(1E)-1- 1215.7 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.58[[(2S,11S)-2-[[(3S,4R)-1- (d, J = 6.5 Hz, 1H), 8.37 (d, J = 7.2 Hz, 1H),carbamoyl-4-[[4-(4-[[(2S)-1- 7.91 (t, J = 9.2 Hz, 2H), 7.42-7.35 (m,8H), [(2S,4R)-4-hydroxy-2-([[4-(4- 7.21-7.15 (m, 6H), 7.11-7.05 (m, 3H),7.06- methyl-1,3-thiazol-5- 6.90 (m, 4H), 6.75 (s, 1H), 5.48 (s, 1H),5.25- yl)phenyl]methyl]carbamoyl) 4.99 (m, 2H), 4.63-4.14 (m, 8H),3.91-3.74 pyrrolidin-1-yl]-3,3-dimethyl-1- (m, 2H), 3.66 (s, 2H),3.10-2.95 (m, 2H), 2.89- oxobutan-2- 2.76 (m, 2H), 2.54-2.51 (m, 2H),2.42 (s, yl]carbamoyl]butyl)phenyl] 3H), 2.32 (d, = 15.3 Hz, 1H),2.20-1.85 (m, methoxy]pentan-3-yl]carbamoyl]-12- 6H), 1.83-172 (s, 1H),1.68-1.40 (m, 7H), oxo-1- 1.06 (m, 3H), 0.96 (s, 9H).azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11- yl]carbamoyl]prop-1-en-2-yl]phenyl]methylphosphonate 74 I-82 diammonium (2-[[(2S,11S)-2- 1214.7(400 MHz, CD₃OD) δ 8.88 (s, 1H), 8.04 (d,[[(3S,4R)-1-carbamoyl-4-[[4-(4- J = 9.4 Hz, 1H), 7.59 (d, J = 3.0 Hz,1H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.51-7.35 (m, 5H), 7.28-7.20 (m,3H), 7.16-7.07 ([[4-(4-methyl-1,3-thiazol-5- (m, 5H), 7.06-7.01 (m, 1H),5.18-5.14 (m, yl)phenyl]methyl]carbamoyl) 1H), 4.81-4.76 (m, 1H), 4.64(s, 1H), 4.61- pyrrolidin-1-yl]-3,3-dimethyl-1- 4.55 (m, 1H), 4.53-4.46(m, 3H), 4.36 (d, J = oxobutan-2- 15.5 Hz, 1H), 4.01-3.96 (m, 1H), 3.91(d, J = yl]carbamoyl]butyl)phenyl]methxy]o 11.1 Hz, 1H), 3.83-3.78 (m,1H), 3.66-3.53 pentan-3-yl]carbamoyl]-12- (m, 1H), 3.53-3.45 (m, 1H),3.27-3.19 (m, oxo-1- 2H), 3.17-3.14 (m, 1H), 3.12-2.99 (m, 2H),azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2.62-2.55(m,2H), 2.48 (s, 3H), 2.40-2.15 (m, 4(13),5,7-trien-11-yl]carbamoyl]- 7H),2.13-2.05 (m, 2H), 1.75-1.57 (m, 5H), 1H-indo1-5-yl)methylphosphonate1.19 (d, J = 6.3 Hz, 3H), 1.04 (s, 9H). 75 I-83 diammonium2-[[(2S,11S)-2- 1229.3 (400 MHz, DMSO-d₆) δ 11.91 (s, 1H), 8.98[[(3S,4R)-1-carbamoyl-4-[[4-(4- (s, 1H), 8.90 (d, J = 1.5 Hz, 1H), 8.59(t, J = [(2S)-1-[(2S,4R)-4-hydroxy-2- 6.1 Hz, 1H), 7.98-7.86 (m, 4H),7.47-7.34 ([[4-(4-methyl-1,3-thiazol- (m, 4H), 7.25-7.13 (m, 2H),7.12-7.04 (m, 4H), 5-yl)phenyl]methyl]carbamoyl) 7.00 (t, J = 7.4 Hz,1H), 6.71 (s, 1H), 5.13- pyrrolidin-1-yl]-3,3-dimethyl-1- 5.07 (m, 2H),4.71-4.60 (m, 1H), 4.55 (d, J = oxobutan-2- 9.3 Hz, 1H), 4.47-4.32 (m,4H), 4.26-4.23 yl]carbamoyl]butyl)phenyl] (m, 2H), 3.82-3.76 (m, 1H),3.70-3.60 (m, methoxy]pentan-3-yl]carbamoyl]-12- 2H), 3.51-3.39 (m, 2H),3.26-3.04 (m, 2H), oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]2.88 (d, J = 16.6 Hz, 1H), 2.54 (d, J = 6.1 Hz,trideca-4(13),5,7-trien-11-yl] 2H), 2.44 (s, 3H), 2.37-1.94 (m, 6H),1.92-1.87 carbamoyl]-1H-indole-5- (m, 1H), 1.77 (d, J = 6.4 Hz, 1H),1.61- carbonylphosphonate 1.41 (m, 6H), 1.08-1.02 (m, 3H), 0.94 (s, 9H).76 I-74 2-[[(2S,11S)-2-[[(3S,4R)-1- 1029.6 (400 MHz, DMSO-d₆) δ 12.13(s, 1H), 11.09 carbamoyl-4-[(4-[4-[1-(2,6- (s, 1H), 9.00 (d, J = 8.1 Hz,1H), 8.82 (d, J = dioxopiperidin-3-yl)-3-methyl-2- 1.6 Hz, 1H),7.98-7.86 (m, 2H), 7.57-7.47 oxo-1,3-benzodiazol-5- (m, 2H), 7.23-7.14(m, 3H), 7.14-7.04 (m, yl]butyl]phenyl)methoxy]pentan- 4H), 7.04-6.93(m, 3H), 6.88-6.80 (m, 1H), 3-yl]carbamoyl]-12-oxo-1- 6.70 (s, 1H),5.35-5.27 (m, 1H), 5.16-5.08 (m, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 1H), 4.72-4.63 (m, 1H), 4.39 (s, 2H), 3.86-4(13),5,7-trien-11-yl]carbamoyl]- 3.78 (m, 2H), 3.31 (s, 3H), 3.26-2.99(m, 2H), 1H-indole-5-carbonylphosphonic 2.98-2.80 (m, 2H), 2.76-2.53 (m,7H), 2.28- acid 2.20 (m, 2H), 2.13-1.96 (m, 3H), 1.76 (d, J = 6.0 Hz,1H), 1.66-1.47 (m, 5H), 1.07 (d, J = 6.2 Hz, 3H). 77 I-85 diammonium2-[[(2S,11S)-2- 1243.8 (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 9.03-[[(3S,4R)-1-carbamoyl-4-[[2-(5- 8.90 (m, 2H), 8.64-8.51 (m, 1H),7.98-7.83 [[(2S)-1-[(2S,4R)-4-hydroxy-2- (m, 3H), 7.52-7.31 (m, 6H),7.29-6.86 (m, 9H), ([[4-(4-methyl-1,3-thiazol-5- 6.71 (s, 1H), 5.14-5.04(m, 2H), 4.72-4.13 yl)phenyl]methyl]carbamoyl) (m, 9H), 3.84-3.76 (m,1H), 3.66 (d, J = 5.4 pyrrolidin-1-yl]-3,3-dimethyl-1- Hz, 2H),3.56-3.43 (m, 2H), 3.23-3.04 (m, 2H), oxobutan-2- 2.89 (d, J = 16.6 Hz,1H), 2.70-2.64 (m, yl]carbamoyl]pentyl)phenyl] 2H), 2.45 (s, 3H),2.35-1.96 (m, 7H), 1.93- methoxy]pentan-3-yl]carbamoyl]-12- 1.70 (m,2H), 1.62-1.42 (m, 5H), 1.33-1.21 (m, oxo-1- 3H), 1.14-1.05 (m, 3H),0.93 (s, 9H). azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]- 1H-indole-5- carbonylphosphonate 78I-86 diammonium 2-[[(2S,11S)-2- 1238.5 (400 MHz, DMSO-d₆) δ 11.92 (s,1H), 9.09- [[(3S,4R)-1-carbamoyl-4-[[4-(5- 8.77 (m, 3H), 8.57 (d, J =6.2 Hz, 1H), 8.01- [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.86 (m, 3H),7.46-7.35 (m, 7H), 7.35-7.21 ( ([[4-(4-methyl-1,3-thiazol-5- m, 5H),7.18 (s, 2H), 7.08 (d, J = 4.7 Hz, 2H), yl)phenyl]methyl]carbamoyl) 6.99(t, J = 7.5 Hz, 1H), 6.69 (s, 1H), 5.11 pyrrolidin-1-yl]-3,3-dimethyl-1-(d, J = 10.6 Hz, 1H), 4.71-4.63 (m, 1H), 4.56oxobutan-2-yl]carbamoyl]pent-1- (d, J = 9.4 Hz, 1H), 4.48-4.39 (m, 4H),4.37- yn-1-yl)phenyl]methoxy]pentan- 4.34 (m, 1H), 4.27-4.20 (m, 1H),3.85-3.63 3-yl]carbamoyl]-12-oxo-1- (m, 2H), 3.49-3.41 (m, 2H),3.30-3.07 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-2H), 2.84 (d, J = 16.6 Hz, 1H), 2.45-2.38 (m,4(13),5,7-trien-11-yl]carbamoyl]- 5H), 2.37-2.15 (m, 4H), 2.12-1.97 (m,3H), 1H-indole-5- 1.92 (d, J = 12.1 Hz, 1H), 1.87-1.70 (m, 3H),carbonylphosphonate 1.61-1.49 (m, 1H), 1.12-1.04 (m, 3H), 0.95 (s, 9H).79 I-87 diammonium 2-[[(2S,11S)-2- 1251.3 (400 MHz, CD₃OD) δ 8.98 (t, J= 1.1 Hz, [[(3S,4R)-1-carbamoyl-4-[[6-(2- 1H), 8.89 (s, 1H), 8.13-8.01(m, 2H), 7.80-7.68 [[(2S)-1-[(2S,4R)-4-hydroxy-2- (m, 3H), 7.62 (s, 1H),7.55-7.38 (m, 6H), ([[4-(4-methyl-1,3-thiazol-5- 7.38-7.28 (m, 2H), 7.11(d, J = 7.6 Hz, 1H), yl)phenyl]methyl]carbamoyl) 7.04-6.88 (m, 2H),5.18-5.12 (m, 1H), 4.82-4.76 pyrrolidin-1-yl]-3,3-dimethyl-1- (m, 1H),4.73-4.43 (m, 6H), 4.40-4.27 (m, oxobutan-2- 1H), 4.09-3.99 (m, 1H),3.90 (d, J = 11.0 Hz, yl]carbamoyl]ethyl)naphthalen-2- 1H), 3.82-3.74(m, 1H), 3.67-3.57 (m, 1H), yl]methoxy]pentan-3- 3.52-3.37 (m, 1H),3.27-3.13 (m, 2H), 3.07 yl]carbamoyl]-12-oxo-1- (t, J = 7.9 Hz, 2H),2.98-2.86 (m, 1H), 2.78- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 2.57 (m, 2H), 2.48 (s, 3H), 2.45-2.17 (m, 44(13),5,7-trien-11-yl]carbamoyl]- H), 2.14-1.98 (m, 2H), 1.79-1.69 (m,1H), 1H-indole-5-carbonylphosphonate 1.25 (d, J = 6.3 Hz, 3H), 0.93 (s,9H). 80 I-88 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1113.3 (400 MHz, DMSO-d₆) δ12.13-11.98 (m, 1H), carbamoyl-1- 11.10 (s, 1H), 8.85-8.70 (m, 2H), 8.40(s, (diphenylmethylcarbamoyl)propyl] 1H), 8.28-8.16 (m, 1H), 7.95 (d, J= 8.7 Hz, carbamoyl]-3-[5-[1-(2,6- 1H), 7.51 (d, J = 8.1 Hz, 1H),7.46-7.38 (m, dioxopiperidin-3-yl)-3-methyl-2- 1H), 7.37-7.19 (m, 11H),7.01-6.93 (m, 2H), oxo-1,3-benzodiazol-4- 6.92-6.87 (m, 1H), 6.82-6.76(m, 1H), 6.10 yl]pentanoyl]-6-oxo- (t, J = 8.0 Hz, 1H), 5.42-5.31 (m,1H), 5.03- octahydropyrrolo[1,2- 4.86 (m, 1H), 4.46 (d, J = 8.6 Hz, 1H),4.41- a][1,5]diazocin-5-yl]carbamoyl]- 4.32 (m, 1H), 4.23-4.14 (m, 1H),3.96 (d, J = 1H-indole-5-carbonylphosphonic 14.7 Hz, 1H), 3.88-3.72 (m,2H), 3.57 (s, 3H), acid 3.01-2.85 (m, 3H), 2.83-2.55 (m, 3H), 2.41- 2.36(m, 2H), 2.23-2.04 (m, 3H), 2.05- 1.94 (m, 4H), 1.93-1.86 (m, 2H),1.84-1.58 (m, 7H). 81 I-89 diammonium [4-[(1E)-1- 1123.6 (400 MHz,CD₃OD) δ 7.75 (d, J = 7.5 Hz, [[(5S,8S,10aR)-8[[(1S)-3- 1H), 7.65-7.59(m, 1H), 7.51 (t, J = 7.7 Hz, carbamoyl-1- 1H), 7.41-7.21 (m, 14H), 6.15(d, J = 9.6 Hz, (diphenylmethylcarbamoyl) 1H), 5.55 (d, J = 5.4 Hz, 1H),5.29-5.08 (m, propyl]carbamoyl]-3-[8-[2-(2,6- 3H), 4.76-4.70 (m, 1H),4.60-4.33 (m, 4H), dioxopiperidin-3-yl)-1-oxo-3H- 4.19-4.10 (m, 1H),3.76 (d, J = 15.7 Hz, 2H), isoindol-4-yl]oct-7-ynoyl]-6-oxo- 3.68-3.40(m, 4H), 3.07-3.01 (m, 1H), 2.99 octahydropyrrolo[1,2- (s, 1H),2.96-2.73 (m, 2H), 2.63-2.31 (m, 7H), a][1,5]diazocin-5- 2.30-2.10 (m,3H), 2.08-1.81 (m, 4H), 1.82- yl]carbamoyl]prop-1-en-2- 1.63 (m, 5H),1.62-1.48 (m, 2H). yl]phenyl]methylphosphonate 82 I-902-[[(2S,11S)-2-[[(3S,4R)-1- 1255.4 (400 MHz, DMSO-d₆) δ 12.10 (s, 1H),8.99 carbamoyl-4-[[4-(4-[[(2S)-1- (d, J = 9.4 Hz, 2H), 8.82 (d, J = 9.0Hz, 2H), [(2S,4R)-4-hydroxy-2-([1-[4-(4- 7.99-7.88 (m, 3H), 7.58-7.47(m, 2H), 7.36- methyl-1,3-thiazol-5- 7.28 (m, 4H), 7.17 (d, J = 8.0 Hz,3H), 7.14- yl)phenyl]cyclopropyl]carbamoyl) 7.08 (s, 4H), 7.02 (d, J =7.3 Hz, 1H), 6.69 pyrrolidin-1-yl]-3,3-dimethyl-1- (s, 1H), 5.12 (d, J =10.6 Hz, 2H), 4.72-4.66 oxobutan-2- (s, 1H), 4.56 (d, J = 9.1 Hz, 1H),4.42-4.33 yl]carbamoyl]butyl)phenyl]methoxy] (m, 4H), 3.85-3.76 (m, 2H),3.68-3.62 (m, 2H), pentan-3-yl]carbamoyl]-12-oxo-1- 2.89 (d, J = 16.8Hz, 1H), 2.68-2.58 (m, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 2H), 2.44 (s, 3H), 2.37-3.30 (s, 2H), 2.29-1.944(13),5,7-trien-11-yl]carbamoyl]- (m, 7H), 1.88-1.68 (m, 2H), 1.61-1.44(m, 1H-indole-5-carbonylphosphonic 5H), 1.28-1.18 (m, 4H), 1.16-1.05 (m,4H), acid 0.94 (s, 9H). 83 I-91 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1155.6 (400MHz, DMSO-d₆) δ 12.28-11.94 (m, 1H), carbamoyl-1- 11.09 (s, 1H),8.86-8.69 (m, 2H), 8.49-8.39 (diphenylmethylcarbamoyl) (m, 1H),8.26-8.14 (m, 1H), 7.95 (d, J = 8.8 propyllcarbamoyl]-3-[8-[1-(2,6- Hz,1H), 7.53 (d, J = 8.8 Hz, 1H), 7.49-7.39dioxopiperidin-3-yl)-3-methyl-2- (m, 1H), 7.38-7.20 (m, 11H), 6.98-6.90(m, oxo-1,3-benzodiazol-4- 2H), 6.90-6.68 (m, 2H), 6.14-6.06 (m, 1H),yl]octanoyl]-6-oxo- 5.40-5.31 (m, 1H), 5.03-4.85 (m, 1H), 4.51-octahydropyrrolo[1,2- 4.15 (m, 4H), 4.07-3.60 (m, 4H), 3.55 (s, 3H),a][1,5]diazocin-5-yl]carbamoyl]- 3.35-3.21 (m, 2H), 2.96-2.81 (m, 3H),2.78- 1H-indole-5-carbonylphosphonic 2.57 (m, 3H), 2.41-2.30 (m, 1H),2.23-2.04 acid (m, 3H), 2.04-1.87 (m, 3H), 1.87-1.68 (m, 2H), 1.67-1.52(m, 6H), 1.42-1.30 (m, 6H). 84 I-92 trifluoroacetic acid; [4-[(1E)-1-1278.9 (400 MHz, CD₃OD) δ 9.07 (d, J = 9.4 Hz, [[(2S,11S)-2-[[(3S,4R)-1-1H), 7.64 (q, J = 8.5 Hz, 4H), 7.41 (q, J = 8.1carbamoyl-4-[[4-(4-[[(2S)-1- Hz, 4H), 7.24 (d, J = 7.7 Hz, 2H),7.17-7.11 [(2S,4R)-4-hydroxy-2-([1-[4-(4- (m, 3H), 7.11-7.06 (m, 2H),6.39 (s, 1H), methyl-1,3-thiazol-5- 5.16 (d, J = 11.0 Hz, 1H), 4.65 (d,J = 16.7 Hz, yl)phenyl]cyclopropyl]carbamoyl) 2H), 4.60-4.44 (m, 4H),4.05 -3.97 (m, 1H), pyrrolidin-1-yl]-3,3-dimethyl-1- 3.91 (d, J = 11.1Hz, 1H), 3.80 (d, J = 8.4 oxobutan-2- Hz, 1H), 3.62-3.54 (m, 1H), 3.49(d, J = 13.5 yl]carbamoyl]butyl)phenyl]methoxy] Hz, 1H), 3.17 (d, J =15.9 Hz, 2H), 3.04 (d, pentan-3-yl]carbamoyl]-12- J = 16.0 Hz, 1H),2.66-2.59 (m, 2H), 2.55 (s, oxo-1- 3H), 2.49 (s, 3H), 2.42-2.14 (m, 6H),2.08- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1.96 (m,2H), 1.72-1.58 (m, 5H), 1.43-1.27 4(13),5,7-trien-11- (m, 5H), 1.20 (d,J = 6.3 Hz, 3H), 1.05 (s, 9H). yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethylphosphonic acid 85 I-93 diammonium [4-[(1E)-1-1265.8 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.49 [[(2S,11S)-2-[[(3S,4R)-1-(d, J = 7.5 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H),carbamoyl-4-[[4-(4-[[(2S)-1- 7.85 (t, J = 10.4 Hz, 2H), 7.62-7.58 (m,4H), [(2S,4R)-4-hydroxy-2-[[(1S)-1-[4- 7.44 (d, J = 8.0 Hz, 2H), 7.38(d, J = 8.0 Hz, (4-methyl-1,3-thiazol-5- 2H), 7.18-7.03 (m, 11H), 6.70(s, 1H), 6.47 yl)phenyl]ethyl]carbamoyl] (s, 1H). 5.18-5.05 (m, 1H),4.96-4.87 (m, pyrrolidin-1-yl]-3,3-dimethyl-1- 1H), 4.60-4.33 (m, 5H),4.28 (d, J = 4.7 Hz, oxobutan-2- 1H), 3.83-3.75 (m, 1H), 3.63-3.57 (m,2H), yl]carbamoyl]butyl)phenyl] 3.47-3.42 (m, 2H), 3.22-3.00 (m, 2H),2.87 (d, methoxy]pentan-3-yl]carbamoyl]-12- J = 16.4 Hz, 1H), 2.58-2.54(m, 2H), 2.46 (s, oxo-1- 3H), 2.35-2.25 (m, 1H), 2.24-1.94 (m, 6H),azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1.78 (d, J = 8.2Hz, 2H), 1.60-1.48 (m, 5H), 4(13),5,7-trien-11- 1.38 (d, J = 7.0 Hz,3H), 1.08 (d, J = 6.2 Hz, yl]carbamoyl]prop-1-en-2- 3H), 0.94 (s, 9H).yl]phenyl] difluoromethylphosphonate 86 I-94 diammonium 2-[[(2S,11S)-2-1243.6 (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.01-[[(3S,4R)-1-carbamoyl-4-[[4-(4- 8.97 (m, 3H), 8.39 (d, J = 7.8 Hz, 1H),8.00- [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.79 (m, 3H), 7.50-7.31 (m, 6H),7.16-6.98 [[(1S)-1-[4-(4-methyl-1,3-thiazol- (m, 9H), 6.70 (s, 1H), 5.12(d, J = 11.0 Hz, 5- 1H), 4.92 (t, J = 7.2 Hz, 1H), 4.69 (d, J = 8.0yl)phenyl]ethyl]carbamoyl] Hz, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.48-4.36pyrrolidin-1-yl]-3,3-dimethyl-1- (m, 3H), 4.32-4.18 (m, 1H), 3.85-3.76(m, oxobutan-2- 1H), 3.61 (s, 2H), 3.46-3.38 (m, 2H), 3.30-3.07yl]carbamoyl]butyl)phenyl] (m, 2H), 2.97-2.83 (m, 1H), 2.48-2.43 (m,methoxy]pentan-3-yl]carbamoyl]-12- 4H), 2.36-2.20 (m, 4H), 2.20-1.96 (m,5H), oxo-1- 1.84-1.68 (m, 2H), 1.58-1.43 (m, 6H), 1.38azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (d, J = 7.0 Hz,3H), 1.08 (d, J = 6.2 Hz, 3H), 4(13),5,7-trien-11-yl]carbamoyl]- 0.93(s, 9H). 1H-indole-5- carbonylphosphonate 87 I-95 diammonium2-[[(2S,11S)-2- 1228.6 (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.10-[[(3S,4R)-1-carbamoyl-4-[[3-(4- 8.85 (m, 2H), 8.65-8.50 (m, 1H),7.98-7.85 [[(2S)-1 -[(2S,4R)-4-hydroxy-2- (m, 2H), 7.76-7.66 (m, 1H),7.46-7.32 (m, 6H), ([[4-(4-methyl-1,3-thiazol-5- 7.22-6.94 (m, 7H), 6.72(s, 1H), 5.16-5.06 yl)phenyl]methyl]carbamoyl) (m, 1H), 4.74-4.63 (m,1H), 4.55 (d, J = 9.1 pyrrolidin-1-yl]-3,3-dimethyl-1- Hz, 1H),4.46-4.38 (m, 5H), 4.23 (t, J = 6.7 oxobutan-2- Hz, 2H), 3.85-3.78 (m,1H), 3.72-3.59 (m, 2H), yl]carbamoyl]butyl)phenyl] 3.55-3.30 (m, 2H),3.01-2.79 (m, 2H), methoxy]pentan-3-yl]carbamoyl]-12- 2.45 (s, 3H),2.34-1.97 (m, 5H), 1.93-1.78 (m, oxo-1- 2H), 1.69 -1.33 (m, 7H), 1.24(s, 3H), 1.17- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-1.03 (m, 9H), 1.02-0.74 (m, 3H). 4(13),5,7-trien-11-yl]carbamoyl]-1H-indole-5- carbonylphosphonate 88 I-96 diammonium 2-[[(2S,11S)-2-1224.5 (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 9.09-[[(3S,4R)-1-carbamoyl-4-[[4-(4- 8.77 (m, 2H), 8.57 (d, J = 6.2 Hz, 1H),8.01- [[(2S)-1 -[(2S,4R)-4-hydroxy-2- 7.86 (m, 1H), 7.46-7.35 (m, 5H),7.35-7.21 ([[4-(4-methyl-1,3-thiazol-5- (m, 5H), 7.20-6.95 (m, 2H), 6.99(t, J = 7.5 yl)phenyl]methyl]carbamoyl) Hz, 1H), 6.69 (s, 1H), 5.11 (d,J = 10.6 Hz, 1H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.71-4.63 (m, 1H),4.56 (d, J = 9.4 Hz, 1H), oxobutan-2-yl]carbamoyl]but-1- 4.48-4.39 (m,5H), 4.27-4.20 (m, 1H), 3.78- yn-1-yl)phenyl]methoxy]pentan- 3.63 (m,2H), 3.49-3.41 (m, 2H), 3.18-3.07 3-yl]carbamoyl]-12-oxo-1- (m, 2H),2.84 (d, J = 16.6 Hz, 1H), 2.45 (s, azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 3H), 2.37- 2.15 (m, 2H), 2.12 -1.97 (m, 4H),4(13),5,7-trien-11-yl]carbamoyl]- 1.92 (d, J = 12.1 Hz, 1H), 1.87-1.70(m, 1H-indole-5- 1H), 1.61-1.49 (m, 1H), 1.26-1.21 (m, 5H), 1.12-carbonylphosphonate 1.04 (m, 3H), 0.95 (s, 9H). 89 I-972-[[(5S,8S,10aR)-8-[[(1S)-3- 1156.1 400 MHz, DMSO-d₆) δ 12.13-12.01 (m,1H), carbamoyl-1- 11.09 (s, 1H), 8.87-8.67 (m, 2H), 8.44 (d,(diphenylmethylcarbamoyl)propyl] J = 6.9 Hz, 1H), 8.26-8.17 (m, 1H),7.95 (d, carbamoyl]-3-[8-[1-(2,6- J = 8.7 Hz, 1H), 7.54 (d, J = 8.8 Hz,1H), dioxopiperidin-3-yl)-3-methyl-2- 7.48-7.42 (m, 1H), 7.37-7.22 (m,11H), 7.03-6.96 oxo-1,3-benzodiazol-5- (m, 2H), 6.87-6.72 (m, 2H),6.13-6.06 (m, yl]octanoyl]-6-oxo- 1H), 5.37-5.25 (m, 1H), 5.02-4.85 (m,1H), octahydropyrrolo[1,2- 4.52-4.14 (m, 3H), 4.13-3.64 (m, 2H), 3.35-a][1,5]diazocin-5-yl]carbamoyl]- 3.27 (m, 6H), 2.96-2.83 (m, 1H),2.77-2.54 1H-indole-5-carbonylphosphonic (m, 5H), 2.48-2.29 (m, 2H),2.18-2.05 (m, 3H), acid 2.04-1.86 (m, 4H), 1.86-1.69 (m, 3H), 1.69- .47(m, 5H), 1.41-1.20 (m, 6H). 90 I-99 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1138.0(400 MHz, DMSO-d₆) δ 12.10-11.98 (m, 1H), carbamoyl-1- 11.12 (s, 1H),8.88-8.69 (m, 2H), 8.41 (d, (diphenylmethylcarbamoyl)propyl] J = 6.8 Hz,1H), 8.28-8.15 (m, 1H), 7.96 (d, carbamoyl]-3-[7-[1-(2,6- J = 8.8 Hz,1H), 7.51 (d, J = 8.7 Hz, 1H), dioxopiperidin-3-yl)-3-methyl-2-7.48-7.38 (m, 1H), 7.38-7.19 (m, 12H), 7.09oxo-1,3-benzodiazol-5-yl]hept-6- (s, 2H) 6.85-6.71 (m, 1H), 6.15-6.06(m, 1H), ynoyl]-6-oxo-octahydropyrrolo[1,2- 5.41-5.34 (m, 1H), 5.06-4.85(m, 1H), 4.52- a][1,5]diazocin-5-yl]carbamoyl]- 4.16 (m, 3H), 4.16-3.63(m, 3H), 3.30 (s, 3H), 1H-indole-5-carbonylphosphonic 3.02-2.83 (m, 1H),2.80-2.53 (m, 5H), 2.47 acid (d, J = 7.1 Hz, 2H), 2.21-2.08 (m, 3H),2.06- 1.96 (m, 3H), 1.95-1.86 (m, 3H), 1.84-1.56 (m, 8H). 91 I-100diammonium 2-[[(2S,11S)-2- 1257.7 (400 MHz, DMSO-d₆) δ 11.95 (s, 1H),9.03- [[(3S,4R)-1-carbamoyl-4-[[4-(6- 8.94 (m, 2H), 8.58 (t, J = 6.0 Hz,1H), 8.06- [(2S)-1-[(2S,4R)-4-hydroxy-2- 7.74 (m, 2H), 7.59-7.29 (m,6H), 7.29-6.90 ([4-(4-methyl-1,3-thiazol-5- (m, 7H), 6.71 (s, 1H),5.21-4.99 (m, 2H), 4.77- yl)phenyl]methyl]carbamoyl) 4.49 (m, 2H),4.49-4.13 (m, 6H), 3.92-3.46 pyrrolidin-1-yl]-3,3-dimethyl-1- (m, 6H),3.26-2.69 (m, 3H), 2.44 (s, 3H), oxobutan-2- 2.32-2.18 (m, 2H),2.16-1.97 (m, 4H), 1.94-1.86 yl]carbamoyl]hexyl)phenyl] (m, 1H),1.82-1.71 (s, 1H), 1.56-1.43 (m, methoxy]pentan-3-yl]carbamoyl]-12- 5H),1.30-1.14 (m, 5H), 1.07 (d, J = 6.1 Hz, oxo-1- 2H), 0.94 (s, 9H).azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]- 1H-indole-5- carbonylphosphonate 92I-101 diammonium 2-[[(2S,11S)-2- 1215.6 (400 MHz, DMSO-d₆) δ 11.96 (s,1H), 9.13- [[(3S,4R)-1-carbamoyl-4-[[4-(3- 8.87 (m, 2H), 8.59 (t, J =6.3 Hz, 1H), 7.99- [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7-87 (m, 2H),7.67-7.33 (m, 6H), 7.33-6.89 ([4-(4-methyl-1,3-thiazol-5- (m, 8H), 6.71(s, 1H), 5.20-5.10 (m, 2H), 4.72- yl)phenyl]methyl]carbamoyl) 4.52 (m,2H), 4.52-4.31 (m, 5H), 4.27-4.17 pyrrolidin-1-yl]-3,3-dimethyl-1- (m,1H), 3.80 (s, 1H), 3.68 (d, J = 3.3 Hz, oxobutan-2- 2H), 3.54-3.44 (m,2H), 3.29-2.62 (m, 2H), yl]carbamoyl]propyl)phenyl] 2.44 (s, 3H),2.37-1.87 (m, 8H), 1.81-1.67 methoxy]pentan-3-yl]carbamoyl]-12- (m, 3H),1.54 (d, J = 11.8 Hz, 1H), 1.34-1.00 oxo-1- (m, 6H), 0.95 (s, 9H).azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]- 1H-indole-5- carbonylphosphonate 93I-102 diammonium 2-[[(5S,8S,10aR)-8- 1150.6 (400 MHz, DMSO-d₆) δ 11.00(s, 1H), 8.88- [[(1S)-3-carbamoyl-1- 8.74 (m, 2H), 8.39-8.03 (m, 2H),7.76-7.42 (diphenylmethylcarbamoyl) (m, 5H), 7.34-7.16 (m, 14H),6.83-6.68 (m, propyl]carbamoyl]-3-[8-[2-(2,6- 1H), 6.14-6.04 (m, 1H),5.17-5.08 (m, 1H), dioxopiperidin-3-yl)-1-oxo-3H- 4.97-4.77 (m, 1H),4.56-4.13 (m, 5H), 4.03- isoindol-4-yl]oct-7-ynoyl]-6-oxo- 3.85 (m, 3H),3.82-3.68 (m, 1H), 2.93-2.80 (m, octahydropyrrolo[1,2- 2H), 2.72-2.55(m, 2H), 2.47-2.28 (m, 2H), a][1,5]diazocin-5-yl]carbamoyl]- 2.21-1.36(m, 21H). 1-methylindole-5- carbonylphosphonate 94 I-1032-[[(5S,8S,10aR)-8-[[(1S)-3- 1141.9 (400 MHz, DMSO-d₆) δ 12.35-11.96 (m,1H), carbamoyl-1- 11.09 (s, 1H), 8.85-8.75 (m, 2H), 8.43 (d,(diphenylmethylcarbamoyl) J = 6.0 Hz, 1H), 8.27-8.18 (m, 1H), 7.96 (d,propy]lcarbamoyl]-3-[7-[1-(2,6- J = 8.6 Hz, 1H), 7.53 (d, J = 9.0 Hz,1H), dioxopiperidin-3-yl)-3-methyl-2- 7.49-7.38 (m, 1H), 7.38 -7.20 (m,11H), 7.05- oxo-1,3-benzodiazol-5- 6.95 (m, 2H), 6.90-6.70 (m, 2H),6.14-5.07 yl]heptanoyl]-6-oxo- (m, 1H), 5.40-5.28 (m, 1H), 5.02-4.83 (m,1H), octahydropyrrolo[1,2- 4.49-4.34 (m, 2H), 4.32-4.16 (m, 1H) 4.06-a][1,5]diazocin-5-yl]carbamoyl]- 3.90 (m, 2H), 3.86-3.75 (m, 2H),3.65-3.35 1H-indole-5-carbonylphosphonic (m, 2H), 3.30 (s, 3H),2.96-2.88 (m, 1H), 2.77- acid 2.54 (m, 4H), 2.49-2.32 (m, 1H), 2.20-2.08(m, 3H), 2.05-1.85 (m, 4H), 1.85-1.71 (m, 4H), 1.69-1.53 (m, 3H),1.45-1.28 (m, 3H). 95 I-104 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1151.8 (400MHz, DMSO-d₆) δ 12.13-12.02 (m, 1H), carbamoyl-1- 11.11 (s, 1H),8.85-8.72 (m, 2H), 8.45-8.40 (diphenylmethylcarbamoyl)propyl] (m, 1H),8.26-8.15 (m, 1H), 8.03-7.84 (m, carbamoyl]-3-[8-[1-(2,6- 1H), 7.57-7.37(m, 2H), 7.37-7.20 (m, 11H), dioxopiperidin-3-yl)-3-methyl-2- 7.08 (d, J= 6.7 Hz, 2H), 6.82-6.65 (m 1H), oxo-1,3-benzodiazol-5-yl]oct-7-6.14-6.08 (m, 1H), 5.42-5.33 (m, 1H), 5.03-ynoyl]-6-oxo-octahydropyrrolo[1,2- 4.88 (m, 1H), 4.50-4.11 (m, 3H),4.00-3.54 a][1,5]diazocin-5-yl]carbamoyl]- (m, 3H), 3.35 (s, 3H), 2.86(d, J = 15.9 Hz, 1H-indole-5-carbonylphosphonic 1H), 2.73-2.56 (m, 3H),2.46-2.34 (m, 3H), acid 2.27-1.13 (m, 18H). 96 I-1052-[[(5S,8S,10aR)-8-[[(1S)-3- 1124.0 ¹H NMR (400 MHz, DMSO-d₆) δ12.30-11.89 carbamoyl-1- (m, 1H), 11.12 (d, J = 7.5 Hz, 1H), 8.86-(diphenylmethylcarbamoyl)propyl] 8.70 (m, 2H), 8.52-8.37 (m, 1H),8.27-8.18 (m, carbamoyl]-3-[6-[1-(2,6- 1H), 7.95 (d, J = 8.8 Hz, 1H),7.53 (d, J = dioxopiperidin-3-yl)-3-methyl-2- 8.8 Hz, 1H), 7.47-7.38 (m,1H), 7.38-7.20 (m, oxo-1,3-benzodiazol-5-yl]hex-5- 12H), 7.15-7.00 (m,2H), 6.84-6.69 (m, 1H), ynoyl]-6-oxo- 6.13-6.05 (m, 1H), 5.42-5.28 (m,1H), 5.07- octahydropyrrolo[1,2- 4.85 (m, 1H), 4.53-4.14 (m, 3H),4.04-3.68 a][1,5]diazocin-5-yl]carbamoyl]- (m, 4H), 3.50-3.35 (m, 2H),3.32 (s, 3H), 2.96- 1H-indole-5-carbonylphosphonic 2.78 (m, 2H),2.76-2.56 (m, 3H), 2.21-1.8 acid 2 (m, 10H), 1.81-1.59 (m, 4H). 97 I-106diammonium 2-[[(5S,8S,10aR)-8- 1123.2 (400 MHz, CD₃OD) δ 7.76-7.69 (m,1H), [[(1S)-3-carbamoyl-1- 7.62-7.55 (m, 2H), 7.52-7.44 (m, 1H),7.40-7.30 (diphenylmethylcarbamoyl)propyl] (m, 6H), 7.30-7.21 (m, 5H),7.02 (d, J = 4.1 carbamoyl]-3-[8-[2-(2,6- Hz, 1H), 6.16 (d, J = 14.1 Hz,1H), 5.27-5.00 dioxopiperidin-3-yl)-1-oxo-3H- (m, 3H), 4.58- 4.39 (m,4H), 4.39-3.90 isoindol-4-yl]oct-7-ynoyl]-6-oxo- (m, 2H), 3.89-3.66 (m,2H), 3.64-3.45 (m, 1H), octahydropyrrolo[1,2- 3.20-3.04 (m, 2H),2.94-2.61 (m, 4H), 2.58- a][1,5]diazocin-5-yl]carbamoyl]- 2.48 (m, 3H),2.39 (t, J = 7.4 Hz, 2H), 2.32- 1H-indole-5- 1.87 (m, 8H), 1.85-1.53 (m,7H). carbonylphosphonate 98 I-107 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1127.9(400 MHz, DMSO-d₆) δ 12.19-12.01 (m, 1H), carbamoyl-1- 11.08 (d, J = 2.9Hz, 1H), 8.84-8.69 (m, 2H), (diphenylmethylcarbamoyl)propyl] 8.43 (d, J= 7.1 Hz, 1H), 8.30-8.18 (m, 1H), carbamoyl]-3-[6-[1-(2,6- 7.95 (d, J =8.7 Hz, 1H), 7.53 (d, J = 8.6 dioxopiperidin-3-yl)-3-methyl-2- Hz, 1H),7.48-7.38 (m, 1H), 7.35-7.21 (m, oxo-1,3-benzodiazol-5- 12H), 7.05-6.93(m, 2H), 6.87 (d, J = 8.1 Hz, yl]hexanoyl]-6-oxo- 1H), 6.80-6.70 (m,1H), 6.08 (d, J = 6.0 Hz, octahydropyrrolo[1,2- 1H), 5.36-5.28 (m, 1H),5.01-4.86 (m, 1H), a][1,5]diazocin-5-yl]carbamoyl]- 4.50-4.12 (m, 3H),3.91 (d, J = 13.4 Hz, 2H), 1H-indole-5-carbonylphosphonic 3.84-3.68 (m,1H), 3.38-3.34 (m, 5H), 2.89 acid (t, J = 13.6 Hz, 1H), 2.75-2.53 (m,5H), 2.19- 2.08 (m, 3H), 2.04-1.88 (m, 4H), 1.83-1.68 (m, 3H), 1.67-1.55(s, 5H), 1.41-1.36 (s, 2H). 99 I-109 diammonium difluoro([4-[(1E)-1-1265.6 (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.05 (d,[[(2S,11S)-2-[[(3S,4R)-4-[[4-(4- J = 9.5 Hz, 1H), 7.69 (d, J = 8.2 Hz,2H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.58 (d, J = 8.2 Hz, 2H), 7.48 (d, J= 8.2 Hz, ([[4-(4-methyl-1,3-thiazol-5- 2H), 7.43 (d, J = 8.2 Hz, 2H),7.23 (d, J = 7.9 yl)phenyl]methyl]carbamoyl) Hz, 2H), 7.13 (d, J = 8.0Hz, 2H), 7.05 (dt, pyrrolidin-1-yl]-3,3-dimethyl-1- J = 14.7, 7.2 Hz,2H), 6.38 (d, J = 1.4 Hz, oxobutan-2- 1H), 5.16-5.12 (m, 1H), 4.72-4.62(m, 2H), yl]carbamoyl]butyl)phenyl]methoxyl- 4.62-4.44 (m, 5H), 4.36 (d,J = 15.6 Hz, 1H), 1-(methylcarbamoyl)pentan- 4.03-3.88 (m, 2H),3.86-3.78 (m, 1H), 3.60- 3-yl]carbamoyl]-12-oxo-1- 3.47 (m, 1H),3.38-3.34 (m, 2H), 3.29-3.13 azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- (m, 3H), 3.06-2.97 (m, 1H), 2.67 (s, 3H), 2.67-4(13),5,7-trien-11- 2.59 (m, 2H), 2.55 (d, J = 1.4 Hz, 3H), 2.49yl]carbamoyl]prop-1-en-2- (s, 3H), 2.37-2.15 (m, 7H), 2.15-1.96 (m, 2H),yl]phenylpmethylphosphonate 1.69-1.58 (m, 5H), 1.34-1.29 (m, 1H), 1.19(d, J = 6.4 Hz, 3H), 1.04 (s, 9H). 100 I-110 diammonium [4-[(1E)-1- 980.2 (400 MHz, CD₃OD) δ 7.69 (d, J = 8.2 Hz, [[(2S,11S)-2-[[(3S,4R)-1-2H), 7.55 (d, J = 8.2 Hz, 2H), 7.12-6.93 (m, 6H), carbamoyl-4-[3-[1-(2,6- 6.36 (d, J = 1.4 Hz, 1H), 5.32 (dd, J = 12.6,dioxopiperidin-3-yl)-3-methyl-2- 5.4 Hz, 1H), 5.18 (dd, J = 10.9, 3.4Hz, oxo-1,3-benzodiazol-5- 1H), 4.70-4.56 (m, 2H), 3.93 (d, J = 11.5 Hz,yl]propoxy]pentan-3- 1H), 3.58-3.49 (m, 2H), 3.47-3.33 (m, 6H),yl]carbamoyl]-12-oxo-1- 3.30-3.05 (m, 2H), 3.02-2.88 (m, 1H), 2.87-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2.71 (m, 4H),2.54 (s, 3H), 2.40-2.25 (m, 3H), 4(13),5,7-trien-11- 2.22-2.10 (m, 1H),2.10-1.98 (m, 1H), 1.89 yl]carbamoyl]prop-1-en-2- (q, J = 6.9 Hz, 2H),1.77-1.58(m, 1H), yl]phenyl]difluoromethylphosphonate 1.17 (d, J = 6.3Hz, 3H). 101 I-111 diammonium 2-[[(5S,8S,10aR)-8- 1137.0 (400 MHz,CD₃OD) δ 8.97 (q, J = 2.3 Hz, [[(1S)-3-carbamoyl-1- 1H), 8.13-8.08 (m,1H), 7.76-7.70 (m, 1H), (diphenylmethylcarbamoyl)propyl] 7.63-7.58 (m,1H), 7.53-7.45 (m, 2H), 7.41- carbamoyl]-3-[8-[2-(2,6- 7.22 (m, 11H),6.16 (d, J = 12.5 Hz, 1H), 5.24- dioxopiperidin-3-yl)-1-oxo-3H- 5.07 (m,2H), 4.60 (d, J = 15.3 Hz, 1H), 4.55- isoindol-4-yl]oct-7-ynoyl]-6-oxo-4.42 (m, 4H), 4.38-3.90 (m, 2H), 3.74 (d, octahydropyrrolo[1,2- J = 10.6Hz, 1H), 3.67-3.49 (m, 1H), 2.97- a][1,5]diazocin-5-yl]carbamoyl]- 2.81(m, 1H), 2.81-2.59 (m, 3H), 2.57-2.48 (m, 1H-indole-5- 3H), 2.40 (t, J =7.4 Hz, 2H), 2.30-2.05 (m, carbonylphosphonate 4H), 2.03-1.88 (m, 3H),1.88-1.55 (m, 8H). 102 I-112 [4-[(1E)-1-[[(5S,8S,10aR)-8- 1164.6 (400MHz, CD₃OD) δ 7.72-7.56 (m, 4H), [(1S)-3-carbamoyl-1- 7.38-7.20 (m,10H), 7.07-6.92 (m, 3H), 6.36 (s, (diphenylmethylcarbamoyl)propyl] 1H),6.15 (d, J = 7.1 Hz, 1H), 5.38-5.32 (m, carbamoyl]-3-[7-[1-(2,6- 1H),5.06-4.90 (m, 1H), 4.57-4.20 (m, 3H), dioxopiperidin-3-yl)-3-methyl-2-4.05-3.77 (m, 2H), 3.71-3.48 (m, 1H), 3.45- oxo-1,3-benzodiazol-5- 3.36(m, 4H), 2.99-2.87 (m, 1H), 2.87-2.75 yl]heptanoyl]-6-oxo- (m, 2H),2.72-2.65 (m, 2H), 2.63-2.56 (m, 1H), octahydropyrrolo[1,2- 2.54 (s,3H), 2.52-2.39 (m, 1H), 2.39-2.07 a][1,5]diazocin-5- (m, 6H), 2.01-1.75(m, 5H), 1.75-1.58 (m, yl]carbamoyl]prop-1-en-2- 4H), 1.57-1.31 (m, 4H).yl]phenyl]difluoromethylphosphonic acid 103 I-113[4-[(1E)-1-[[(5S,8S,10aR)-8- 1178.7 (400 MHz, CD₃OD) δ 7.68-7.55 (m,4H), [[(1S)-3-carbamoyl-1- 7.39-7.22 (m, 10H), 7.06-6.92 (m, 3H), 6.39-(diphenylmethylcarbamoyl)propyl] 6.32 (m, 1H), 6.15 (d, J = 10.6 Hz,1H), 5.36- carbamoyl]-3-[8-[1-(2,6- 5.26 (m, 1H), 5.09-4.94 (m, 2H),4.50-4.23 dioxopiperidin-3-yl)-3-methyl-2- (m, 3H), 4.03-3.47 (m, 3H),3.40 (s, 3H), oxo-1,3-benzodiazol-5- 2.99-2.88 (m, 1H), 2.87-2.76 (m,2H), 2.72- yl]octanoyl]-6-oxo- 2.68 (m, 2H), 2.63-2.57 (m, 1H),2.55-2.50 (m, octahydropyrrolo[1,2- 4H), 2.43-2.30 (m, 2H), 2.30-2.05(m, 4H), a][1,5]diazocin-5- 2.03-1.89 (m, 4H), 1.83-1.72 (m, 1H), 1.71-yl]carbamoyl]prop-1-en-2- 1.59 (m, 4H), 1.49-1.32 (m, 6H).yl]phenyl]difluoromethylphosphonic acid 104 I-114[4-[(1E)-1-[[(5S,8S,10aR)-8- 1150.5 (400 MHz, CD₃OD) δ 7.69-7.55 (m,4H), [[(1S)-3-carbamoyl-1- 7.40-7.21 (m, 10H), 7.09-6.93 (m, 3H), 6.36(s, (diphenylmethylcarbamoyl)propyl] 1H), 6.18-6.07 (m, 1H), 5.38-5.27(m, 1H), carbamoyl]-3-[6-[1-(2,6- 5.04-4.93 (s, 1H), 4.53-4.23 (m, 3H),4.07-3.47 dioxopiperidin-3-yl)-3-methyl-2- (m, 3H), 3.46-3.34 (d, J =6.9 Hz, 3H), oxo-1,3-benzodiazol-5- 3.01-2.52 (m, 8H), 2.48-2.03 (m,9H), 2.01- yl]hexanoyl]-6-oxo- 1.61 (m, 9H), 1.50-1.38 (m, 2H).octahydropyrrolo[1,2- a][1,5]diazocin-5- yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethylphosphonic acid 105 I-115((4-((E)-4-(((5S,8S,10aR)-8-(((S)- 1160.6 (400 MHz, CD₃OD) δ 7.77-7.72(m, 1H), 5-amino-1-(benzhydrylamino)- 7.71-7.66 (m, 2H), 7.63-7.58 (m,1H), 7.57- 1,5-dioxopentan-2-yl)carbamoyl)- 7.46 (m, 3H), 7.38-7.21 (m,10H), 6.38-6.29 3-(8-(2-(2,6-dioxopiperidin-3-yl)- (m, 1H), 6.15 (d, J =8.9 Hz, 1H), 5.22-5.11 1-oxoisoindolin-4-yl)oct-7- (m, 1H), 5.09-4.93(m, 1H), 4.53-4.42 (m, 4H), ynoyl)-6- 4.32-4.01 (m, 1H), 3.86 (d, J =14.5 Hz, oxodecahydropyrrolo[1,2- 1H), 3.80-3.64 (m, 1H), 3.65-3.49 (m,1H), a][1,5]diazocin-5-yl)amino)-4- 3.49-3.35 (m, 2H), 2.95-2.83 (m,1H), 2.82-2.72 oxobut-2-en-2- (m, 1H), 2.70-2.58 (m, 2H), 2.57-2.46 (m,yl)phenyl)difluoromethyl) 6H), 2.46-2.30 (m, 2H), 2.30-2.07 (m, 4H),phosphonic acid 2.01-1.86 (s, 3H), 1.82-1.68 (m, 5H), 1.65-1.54 (m, 2H).106 I-117 (2-(((3S,6S)-6-(((2R,3S)-6- 1242.6 (400 MHz, DMSO-d₆) δ 12.02(s, 1H), 8.90- amino-2-((4-(6-(((S)-1-((2S,4R)- 8.86 (m, 2H), 8.56 (s,1H), 7.85 (d, J = 9.5 Hz, 4-hydroxy-2-((4-(4- 2H), 7.49-7.33 (m, 6H),7.29-6.61 (m, 8H), methylthiazol-5- 5.15-5.05 (m, 2H), 4.54-4.50 (m,1H), 4.49- yl)benzyl)carbamoyl)pyrrolidin- 4.30 (m, 5H), 4.22 (d, J =16.1 Hz, 1H), 1-yl)-3,3-dimethyl-1-oxobutan-2- 3.89-3.75 (m, 3H),3.68-3.56 (d, J = 15.6 Hz, yl)amino)-6- 2H), 3.26-3.04 (m, 2H),2.89-2.78 (m, 1H), oxohexyl)benzyl)oxy)-6- 2.45 (s, 3H), 2.37-1.95 (m,6H), 1.92-1.73 oxohexan-3-yl)carbamoyl)-4-oxo- (m, 2H), 1.62-1.42 (m,5H), 1.32-1.15 (m, 5H), 1,2,3,4,6,7- 1.12-1.00 (m, 2H), 0.93 (s, 9H).hexahydroazepino[3,2,1-hi]indol- 3-yl)carbamoyl)-1H-indole-5-carbonyl)phosphonic acid 107 I-118 diammonium 2-[[(2S,11S)-2- 1057.5(400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 11.08[[(3S,4R)-1-carbamoyl-4-[(4-[6- (s, 1H), 9.12-9.05 (m, 1H), 8.26-7.80(m, 2H), [1-(2,6-dioxopiperidin-3-yl)-3- 7.66-7.35 (m, 2H), 7.35-6.51(m, 13H), methyl-2-oxo-1,3-benzodiazol-5- 5.42-5.27 (m, 1H), 5.13-4.98(m, 1H), 4.72- yl]hexyl]phenyl)methoxy]pentan- 4.60 (m, 1H), 4.38 (s,2H), 3.86-3.72 (m, 1H), 3-yl]carbamoyl]-12-oxo-1- 3.34 (s, 2H),3.31-3.00 (m, 5H), 2.97-2.79 azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- (m, 2H), 2.76-2.55 (m, 5H), 2.39-1.88 (m, 5H),4(13),5,7-trien-11-yl]carbamoyl]- 1.78-1.73 (m, 1H), 1.59-1.52 (m, 5H),1H-indole-5- 1.32-1.22 (m, 5H), 1.07 (d, J = 8.4 Hz, 3H).carbonylphosphonate 108 I-119 [4-[(1E)-1-[[(2S,11S)-2-[[(3S,4R)- 1251.60(400 MHz, CD₃OD) δ 8.93-8.86 (m, 1H), 1-carbamoyl-4-[[4-(4-[[(2S)-1-7.76-7.69 (m, 2H), 7.62-7.56 (m, 2H), 7.50-[(2S,4S)-4-hydroxy-2-([[4-(4- 7.39 (m, 4H), 7.29-7.23 (m, 2H), 7.15-7.06(m, methyl-1,3-thiazol-5- 2H), 7.07 (d, J = 7.0 Hz, 1H), 7.07-6.99 (m,yl)phenyl]methyl]carbamoyl) 1H), 6.37 (d, J = 1.5 Hz, 1H), 5.16 (dd, J =pyrrolidin-1-yl]-3,3-dimethyl-1- 10.9, 3.4 Hz, 1H), 4.69-4.62 (m, 1H),4.60- oxobutan-2- 4.40 (m, 5H), 4.42-4.34 (m, 2H), 4.06-3.97xy]pentan-3-yl]carbamoyl]-12- (m, 2H), 3.75-3.68 (m, 1H), 3.61-3.44 (m,2H), oxo-l- 3.28-3.15 (m, 1H), 3.06-3.29 (m, 1H), 2.62azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (s, 3H), 2.55(d, J = 1.3 Hz, 3H), 2.49 (s, 4(13),5,7-trien-11- 3H), 2.45-2.13 (m,7H), 2.03-1.94 (m, 1H), yl]carbamoyl]prop-1-en-2- 1.67-1.61 (m, 6H),1.19 (d, J = 6.3 Hz, 3H), yl]phenyl]difluoromethylphosphonic 1.04 (s,9H) acid 109 I-120 diammonium 2-[[(5S,8S,10aR)-8- 1150.75 (400 MHz,DMSO-d₆) δ 11.96-11.83 (m, 1H), [[(1S)-3-carbamoyl-1- 9.16-8.58 (m, 2H),8.50-7.89 (m, 2H), 7.75- (diphenylmethylcarbamoyl)propyl] 7.39 (m, 5H),7.39-7.19 (m, 12H), 6.80- carbamoyl]-3-[8-[2-(1-methyl- 6.76 (m, 1H),6.11-6.09 (m, 1H), 5.21-5.18 (m, 2,6-dioxopiperidin-3-yl)-1-oxo- 1H),4.97-4.95 (m, 1H), 4.57-4.22 (m, 5H), 3H-isoindol-4-yl]oct-7-ynoyl]-6-4.18-4.16 (m, 1H), 3.94-3.92 (m, 1H), 3.78- oxo-octahydropyrrolo[1,2-3.76 (m, 1H), 3.16-2.89 (m, 4H), 2.78-2.62a][1,5]diazocin-5-yl]carbamoyl]- (m, 2H), 2.42-1.30 (m, 1H), 2.35-2.33(m, 1H-indole-5- 3H), 2.21-1.84 (m, 10H), 1.84-1.33 (m, 10H)carbonylphosphonate 110 I-121 diammonium 2-[[(2S,11S)-2- 1228.55 (400MHz, DMSO-d₆) δ 11.86 (s, 1H), 9.02- [[(3S,4R)-1-carbamoyl-4-[[4-(4-8.91 (m, 2H), 8.68-8.64 (m, 1H), 7.98-7.85[[(2S)-1-[(2S,4S)-4-hydroxy-2- (m, 3H), 7.45-7.35 (m, 6H), 7.26-6.90 (m,9H), ([[4-(4-methyl-1,3-thiazol-5- 6.70 (s, 1H), 5.47-5.43 (m, 1H),5.14-5.09 yl)phenyl]methyl]carbamoyl) (m, 1H) 4.72-4.63 (m, 1H),4.50-4.32 (m, 6H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.31-4.28 (m, 1H),4.26-4.15 (m, 2H), oxobutan-2- 3.95-3.91(m, 1H), 3.85-3.72(m, 1H),3.51-3.45 yl]carbamoyl]butyl)phenyl] (m, 4H), 3.25-3.10 (m, 1H),2.92-2.88 (m, methoxy]pentan-3-yl]carbamoyl]-12- 1H), 2.45 (s, 3H),2.10-1.98 (m, 4H), 1.80-1.65 oxo-1- (m, 3H), 1.60-1.48 (m, 6H),1.28-1.23 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-3H), 1.03-1.01 (m, 3H), 0.91 (s, 9H) 4(13),5,7-trien-11-yl]carbamoyl]-1H-indole-5- carbonylphosphonate 111 I-122 2-[[(5S,8S,10aR)-8-[[(1S)-3-[(M − 1)]⁻ = (400 MHz, DMSO-d₆) δ 12.28-11.99 (m, 1H), carbamoyl-1-1097.15 11.09 (s, 1H), 8.85-8.70 (m, 2H), 8.47-8.42(diphenylmethylcarbamoyl)propyL] (m, 1H), 8.26-8.14 (m, 1H), 7.99-7.93(m, carbamoyl]-3-[4-[1-(2,6- 1H), 7.56-7.51 (m, 1H), 7.47-7.41 (m, 1H),dioxopiperidin-3-yl)-3-methyl-2- 7.36-7.22 (m, 11H), 7.01-6.85 (m, 3H),6.81- oxo-1,3-benzodiazol-4- 6.77 (m, 1H), 6.17-6.04 (m, 1H), 5.42-5.29yl]butanoyl]-6-oxo- (m, 1H), 5.05-4.88 (m, 1H), 4.52-4.13 (m,octahydropyrrolo[1,2- 4H), 4.10-3.90 (m, 2H), 3.83-3.70 (m, 2H),a][1,5]diazocin-5-yl]carbamoyl]- 3.59 (s, 3H), 3.04-2.76 (m, 5H),2.75-2.55 (m, 1H-indole-5- 3H), 2.23-2.07 (m, 3H), 2.05-1.95 (m, 3H),carbonylphosphonic acid 1.94-1.85 (m, 3H), 1.84-1.60 (m, 4H) 112 I-1232-[[(5S,8S,10aR)-8-[[(1S)-3- [(M − 1)]⁻ = (400 MHz, DMSO-d₆) δ12.24-12.91 (m, 1H ), carbamoyl-1- 1125.25 11.09 (s, 1H), 8.90-8.71 (m,2H), 8.46-8.13 (diphenylmethylcarbamoyl)propyl] (m, 2H), 8.00-7.93(m,1H), 7.54-7.20 (m, carbamoyl]-3-[6-[1-(2,6- 13H), 7.02-6.76 (m, 4H),6.12-6.07 (m, 1H), dioxopiperidin-3-yl)-3-methyl-2- 5.40-5.32 (m, 1H),5.01-4.84 (m, 1H), 4.49- oxo-1,3-benzodiazol-4- 4.42 (m, 1H), 4.41-4.34(m, 1H), 4.23-4.14 yl]hexanoyl]-6-oxo- (m, 1H), 3.99-3.87 (m, 1H),3.83-3.71 (m, 2H), octahydropyrrolo[1,2- 3.55 (s, 3H), 3.13-3.00 (m,1H), 2.94-2.83 a][1,5]diazocin-5-yl]carbamoyl]- (m, 3H), 2.75-2.60 (m,3H), 2.25-1.86 (m, 1H-indole-5-carbonylphosphonic 8H), 1.84-1.70 (m,3H), 1.69-1.54 (m, 5H), acid 1.52-1.36 (m, 2H), 1.26-1.12 (m, 2H) 113I-124 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1141.30 (400 MHz, DMSO-d₆) δ12.17-11.96 (m, 1H), carbamoyl-1- 11.09 (s, 1H), 8.84-8.75 (m, 2H), 8.43(d, (diphenylmethylcarbamoyl)propyl] J = 6.8 Hz, 1H), 8.24-8.16 (m, 1H),7.96 (d, carbamoyl]-3-[7-[1-(2,6- J = 8.7 Hz, 1H), 7.51 (d, J = 8.8 Hz,1H), dioxopiperidin-3-yl)-3-methyl-2- 7.46-7.41 (m, 1H), 7.40-7.20 (m,11H), 6.99-6.89 oxo-1,3-benzodiazol-4- (m, 2H), 6.89-6.82 (m, 1H), 6.79(s, 1H), yl]heptanoyl]-6-oxo- 6.12-6.08 (m, 1H), 5.36 (d, J = 8.3 Hz,1H), octahydropyrrolo[1,2- 5.06-4.88 (m, 1H), 4.50-4.43 (m, 1H), 4.38a][1,5]diazocin-5-yl]carbamoyl]- (d, J = 6.9 Hz, 1H), 4.22-4.17 (m, 1H),4.02- 1H-indole-5-carbonylphosphonic 3.86 (m, 1H), 3.83-3.74 (m, 2H),3.55 (s, 3H), acid 3.15-3.05 (m, 2H), 2.88-2.76 (m, 4H), 2.66- 2.58 (m,3H), 2.18-2.08 (m, 3H), 2.04-1.89 (m, 4H), 1.84-1.71 (m, 2H), 1.66-1.55(m, 6H), 1.50-1.31 (m, 4H), 1.25-1.15 (m, 1H). 114 I-1252-[[(5S,8S,10aR)-8-[[(1S)-3- 1169.35 (400 MHz, DMSO-d₆) δ 12.13-12.08(m, 1H), carbamoyl-1- 11.09 (s, 1H), 8.85-8.72 (m, 2H), 8.43 (d,(diphenylmethylcarbamoyl)propyl] J = 6.6 Hz, 1H), 8.27-8.19 (m, 1H),7.96 (d, carbamoyl]-3-[9-[1-(2,6- J = 8.9 Hz, 1H), 7.62-7.16 (m, 13H),6.96 (d, dioxopiperidin-3-yl)-3-methyl-2- J = 6.3 Hz, 2H), 6.93-6.66 (m,2H), 6.14-6.06 oxo-1,3-benzodiazol-4- (m, 1H), 5.36-5.34 (m, 1H),4.96-3.92 (m, yl]nonanoyl]-6-oxo- 1H), 4.49-4.40 (m, 1H), 4.41-4.34 (m,1H), octahydropyrrolo[1,2- 4.23-4.14 (m, 1H), 4.04-3.86 (m, 1H), 3.83-a][1,5]diazocin-5-yl]carbamoyl]- 3.74 (m, 2H), 3.55 (s, 3H), 3.15-3.10(m, 1H), 1H-indole-5-carbonylphosphonic 2.96-2.82 (m, 3H), 2.80-2.74 (m,1H), 2.67- acid 2.58 (m, 2H), 2.18-2.11 (m, 4H), 2.05-1.86 (m, 4H),1.82-1.74 (m, 3H), 1.70-1.44 (m, 6H), 1.38-1.30 (m, 7H), 1.25-1.13 (m,2H) 115 I-126 diammonium 2-[[(2S,11S)-2- 1251.85 (400 MHz, DMSO-d₆) δ11.92 (s, 1H), 9.01- [[(3S,4R)-1-carbamoyl-4-[[7-(2- 8.96 (m, 2H),8.59-5.57 (m, 1H), 8.07-7.60 [(2S)-1-[(2S,4R)-4-hydroxy-2- (m, 6H),7.49-7.15 (m, 8H), 7.11-6.66 (m, 4H), ([[4-(4-methyl-1,3-thiazol-5-5.13-5.10 (m, 1H), 4.68-4.66 (m, 1H), 4.63- yl)phenyl]methyl]carbamoyl)4.54 (m, 2H), 4.49-4.40 (m, 2H), 4.37-4.35pyrrolidin-1-yl]-3,3-dimethyl-1- (m, 1H), 4.26-4.18 (m, 1H), 3.84-3.82(m, oxobutan-2- 1H), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 6H),yl]carbamoyl]ethyl)naphthalen-2- 3.14-3.10 (m, 3H), 3.01-2.89 (m, 2H),2.86- yl]methoxy]pentan-3- 2.82 (m, 2H), 2.74-2.70 (m, 1H), 2.70-2.62yl]carbamoyl]-12-oxo-1- (m, 1H), 2.44 (s, 3H), 2.25-2.21 (m, 2H), 2.10-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2.04 (m, 2H),1.95-1.87 (m, 1H), 1.79-1.75 4(13),5,7-trien-11-yl]carbamoyl]- (m, 1H),1.59-1.57 (m, 1H), 1.32-1.18 (m, 1H-indole-5- 2H), 1.11 (d, J = 6.2 Hz,3H), 0.89 (m, 9H) carbonylphosphonate 116 I-127 diammonium2-[[(2S,11S)-2- 1264.60 (400 MHz, DMSO-d₆) δ 12.01-11.80 (m, 1H),[[(3S,4R)-1-carbamoyl-4-[[6-(3- 9.09-8.91 (m, 2H), 8.58 (d, J = 6.7 Hz,1H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.93-7.91 (m, 2H), 7.75 (d, J = 9.4Hz, 2H), ([[4-(4-methyl-1,3-thiazol-5- 7.63 (d, J = 13.5 Hz, 1H),7.50-7.15 (m, yl)phenyl]methyl]carbamoyl) 11H), 7.03-6.98 (m, 3H), 6.69(d, J = 14.4 Hz, pyrrolidin-1-yl]-3,3-dimethyl-1- 2H), 5.38-5.29 (m,1H), 5.12 (d, J = 14.3 Hz, oxobutan-2- 1H), 4.68-4.60 (m, 1H), 4.58 (d,J = 10.2 yl]carbamoyl]propyl)naphthalen- Hz, 2H), 4.49-4.40 (m, 1H),4.36 (s, 1H), 2-yl]methoxy]pentan-3- 4.23-4.19 (m, 1H), 3.82 (s, 1H),3.69 (s, 1H), yl]carbamoyl]-12-oxo-1- 3.50-3.35 (m 4H), 2.95-2.82(m,1H), 2.76-2.74 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-(m, 1H), 2.48 (s, 3H), 2.39-2.22 (m, 4H),4(13),5,7-trien-11-yl]carbamoyl]- 2.05-1.98 (m, 3H), 1.97-1.75 (m, 4H),1.76- 1H-indole-5- 1.50 (m, 2H), 1.46-1.11 (m, 10H), 1.01-0.82carbonylphosphonate (m, 7H) 117 I-129 diammonium 2-[[(2S,11S)-2- 1240.55(400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 9.01- [[(3S,4R)-1-carbamoyl-4-([4-8.92 (m, 2H), 8.86-8.84 (m, 1H), 8.57 (t, J =[(1E)-5-[[(2S)-1-[(2S,4R)-4- 6.1 Hz, 1H), 8.01-7.84 (m, 3H), 7.54-7.35 (hydroxy-2-([[4-(4-methyl-1,3- (m, 7H), 7.35-7.23 (m, 3H), 7.22-7.19 (m,3H), thiazol-5- 7.11-6.97 (m, 4H), 6.69 (s, 1H), 6.45-6.18yl)phenyl]methyl]carbamoyl) (m, 2H), 5.13-5.09 (m, 1H), 4.70-4.65 (m,pyrrolidin-1-yl]-3,3-dimethyl-1- 1H), 4.57 (d, J = 9.3 Hz, 1H),4.50-4.32 (m, oxobutan-2-yl]carbamoyl]pent-1- 6H), 4.25-4.20 (m, 1H),3.82-3.76 (m, 2H), en-l-yl]phenyl]methoxy)pentan- 3.70-3.65 (m, 2H),3.30-3.00 (m, 1H), 2.88- 3-yl]carbamoyl]-12-oxo-1- 2.84 (m, 1H),2.72-2.56 (m, 1H), 2.45 (s, 3H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 2.38-2.11 (m, 6H), 2.09-1.99 (m, 3H), 1.94-4(13),5,7-trien-11-yl]carbamoyl]- 1.88 (m, 1H), 1.85-1.45 (m, 2H),1.42-1.12 1H-indole-5- (m, 2H), 1.08 (d, J = 6.2 Hz, 3H), 0.95 (s, 9H)carbonylphosphonate 118 I-130 diammonium 2-[[(2S,11S)-2- 1227.50 (400MHz, DMSO-d₆) δ 11.91 (s, 1H), 8.99- [[(3S,4R)-1-carbamoyl-4-([4- 8.90(m, 3H), 8.58 (t, J = 5.9 Hz, 1H), 8.07 - [(1E)-4-[[(2S)-1-[(2S,4R)-4-7.80 (m, 3H), 7.48-7.34 (m, 7H), 7.34-7.14 hydroxy-2-([[4-(4-methyl-1,3-(m, 6H), 7.14-7.04 (m, 2H), 7.00 (t, J = 7.4 thiazol-5- Hz, 1H), 6.70(s, 1H), 6.41-6.36 (m, 1H), 6.32- yl)phenyl]methyl]carbamoyl) 6.15 (m,1H), 5.13-5.10 (m, 1H), 4.70-4.65 pyrrolidin-1-yl]-3,3-dimethyl-1- (m1H) 4.57 (d, J = 9.4 Hz, 1H), 4.49-4.30 oxobutan-2-yl]carbamoyl]but-1-(m, 6H), 4.24-4.19 (m, 1H), 3.83-3.76 (m, en-1-yl]phenyl]methoxy)pentan-1H), 3.70-3.63 (m, 2H), 3.22-3.06 (m, 5H), 3-yl]carbamoyl]-12-oxo-1-2.89-2.84 (m, 1H), 2.76-2.60 (m, 1H), 2.44 (s,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 3H), 2.42-2.37(m, 1H), 2.36-2.14 (m, 2H), 4(13),5,7-trien-11-yl]carbamoyl]- 2.10-1.98(m, 3H), 1.95-1.83 (m, 1H), 1.80- 1H-indole-5-carbonylphosphonate 1.72(m, 1H), 1.60-1.49 (m, 1H), 1.25-1.15 (m, 1H), 1.07 (d, J = 6.2 Hz, 3H),0.93 (s, 9H). 119 I-133 diammonium 2-[[(2S,11S)-2- 1264.70 (400 MHz,DMSO-d₆) δ 11.87 (s, 1H), 8.99- [[(3S,4R)-1-carbamoyl-4-[[5-(3- 8.93 (m,3H), 8.59 (t, J = 6.2 Hz, 1H), 8.00 [[(2S)-1-[(2S,4R)-4-hydroxy-2- (d, J= 8.9 Hz, 2H), 7.94 (t, J = 8.2 Hz, 2H), ([[4-(4-methyl-1,3-thiazol-5-7.80 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.46-7.38yl)phenyl]methyl]carbamoyl) (m, 8H), 7.32 (d, J = 7.1 Hz, 1H), 7.21 (s,pyrrolidin-1-yl]-3,3-dimethyl-1- 1H), 7.11-7.09 (m, 1H), 6.98-6.96 (m,2H), oxobutan-2- 6.72 (s, 1H), 5.14-5.10 (m, 1H), 4.73-4.53yl]carbamoyl]propyl)naphthalen- (m, 4H), 4.50-4.40 (m, 2H), 4.37-4.35(m, 1H), 2-yl]methoxy]pentan-3- 4.26-4.20 (m, 1H), 3.88-3.82 (m, 1H),3.72- yl]carbamoyl]-12-oxo-1- 3.67 (m, 2H), 3.57-3.50 (m, 1H), 3.21-3.13azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m, 1H),3.04-2.98 (m, 2H), 2.86-2.82 (m, 4(13),5,7-trien-11-yl]carbamoyl]- 1H),2.45 (s, 3H), 2.43-2.37 (m, 1H), 2.37-2.17 1H-indole-5- (m, 3H),2.16-1.97 (m, 3H), 1.97-1.72 (m, carbonylphosphonate 3H), 1.66-1.45 (m,1H), 1.30-1.23 (m, 6H), 1.13 (d, J = 6.2 Hz, 3H), 0.97 (s, 9H) 120 I-136diammonium 2-[[(2S,11S)-2- 1250.55 (400 MHz, DMSO-d₆) δ 11.85 (s, 1H),8.98 [[(3S,4R)-1-carbamoyl-4-[[5-(2- (s, 1H), 8.94-8.91 (m, 2H),8.63-8.61 (m, 1H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 8.10 (d, J = 9.4 Hz,1H), 7.98 (d, J = 8.7 ([[4-(4-methyl-1,3-thiazol-5- Hz, 1H), 7.93-7.90(m, 2H), 7.80 (s, 1H), 7.70 yl)phenyl]methyl]carbamoyl) (d, J = 7.6 Hz,1H), 7.45-7.35 (m, 11H), 7.0- pyrrolidin-1-yl]-3,3-dimethyl-1- 7.05 (m,2H), 7.01-6.95 (m, 2H), 6.72 (s, 1H), oxobutan-2- 5.14-5.11 (m, 1H),4.70-4.61 (m, 4H), yl]carbamoyl]ethyl)naphthalen-2- 4.50-4.37 (m, 3H),4.25-4.21 (m, 1H), 3.87- yl]methoxy]pentan-3- 3.85 (m, 1H), 3.72-3.69(m, 2H), 3.55-3.51(m, yl]carbamoyl]-12-oxo-1- 2H), 3.25-3.18 (m, 2H),2.87-2.85 (m, 1H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 2.46 (s, 3H), 2.24-2.21 (m, 1H), 2.10-2.054(13),5,7-trien-11-yl]carbamoyl]- (m, 2H), 1.91-1.75 (m, 2H), 1.76 (s,3H), 1.58- 1H-indole-5- 1.56 (m, 1H), 1.26-1.22 (m, 3H), 1.17-1.12carbonylphosphonate (m, 4H), 0.94 (s, 9H) 121 I-137 diammonium2-[[(2S)-1- 1222.95 (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 8.99[(1R,2S,5S)-2-[[(3S,4R)-1- (s, 1H), 8.85 (s, 1H), 8.72-8.70 (m, 1H),8.58- carbamoyl-4-[[4-(4-[[(2S)-1- 8.56 (m, 1H), 7.95-7.89 (m, 1H), 7.63(d, [(2S,4R)-4-hydroxy-2-([[4-(4- J = 9.2 Hz, 1H), 7.44-7.38 (m, 8H),7.24 (d, methyl-1,3-thiazol-5- J = 7.7 Hz, 2H), 7.14 (d, J = 7.7 Hz,2H), yl)phenyl]methyl]carbamoyl) 7.07 (s, 1H), 6.70 (s, 1H), 5.20-5.17(m, 1H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.70-4.68 (m, 1H), 4.57-4.53(m, 1H), 4.51- oxobutan-2- 4.39 (m, 5H), 4.36-4.34 (m, 1H), 4.24-4.20yl]carbamoyl]butyl)phenyl]methoxy] (m, 1H), 4.07-4.05 (m, 1H), 3.75-3.65(m, 5H), pentan-3-yl]carbamoyl]-3- 2.55-2.51 (m, 2H), 2.45 (s, 3H),2.35-2.32 azabicyclo[3.1.0]hexan-3-yl]-4- (m, 3H), 2.20-2.01 (m, 3H),1.95-1.83 (m, methyl-1-oxopentan-2- 3H), 1.82-1.75 (m, 4H), 1.69-1.52(m, 6H), yl]carbamoyl]-1H-indole-5- 1.25-1.24 (m, 2H), 1.09 (d, J = 6.2Hz, 3H), carbonylphosphonate 0.94-0.90 (m, 12H), 0.77-0.73 (m, 1H),0.62-0.57 (m, 1H) 122 I-138 diammonium 2-[[(2S,11S)-2- 1214.60 (400 MHz,DMSO-d₆) δ 11.91 (s, 1H), 8.99 [(1S)-3-carbamoyl-1-([[4-(3- (s, 1H),8.96-8.89 (m, 1H), 8.60-8.57 (m, 1H), [[(2S)-1-[(2S,4R)-4-hydroxy-2-8.36-8.34 (m, 1H), 8.26 (d, J = 7.8 Hz, 1H),([[4-(4-methyl-1,3-thiazol-5- 7.94 (dd, J = 8.6, 1.5 Hz, 2H), 7.53-7.42yl)phenyl]methyl]carbamoyl) (m, 6H), 7.33-7.28 (m, 3H), 7.13-7.04 (m,6H) pyrrolidin-1-yl]-3,3-dimethyl-1- 7.14-7.00 (m, 1H), 6.81-6.69 (m,1H), 5.20- oxobutan-2- 5.02 (m, 2H), 4.68-4.60 (m, 1H), 4.56 (d,yl]carbamoyl]propyl)phenyl]meth J = 9.3 Hz, 1H), 4.52-4.40 (m, 2H),4.37-4.33 yl]carbamoyl)propyl]carbamoyl]- (m, 1H), 4.30-4.18 (m, 5H),3.68-3.65 (m, 12-oxo-1- 2H), 3.48-3.45 (m, 2H), 3.32-3.28 (m, 2H),azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 3.15-3.11 (m,2H), 3.09-2.97 (m, 1H), 2.45 4(13),5,7-trien-11-yl]carbamoyl]- (s, 3H),2.32-2.01 (m, 6H), 1.98-1.86 (m, 2H), 1H-indole-5- 1.82-1.76 (m, 3H),0.95 (s, 9H) carbonylphosphonate 123 I-139 diammonium 2-[[(2S,11S)-2-1227.55 (400 MHz, DMSO-d₆) δ 12.01-11.92 (m, 1H),[(1S)-3-carbamoyl-1-([[4-(4- 9.03-8.96 (m, 1H), 8.94 (d, J = 8.2 Hz,1H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 8.92-8.86 (m, 2H), 8.63-8.58 (m,1H), 8.01- ([[4-(4-methyl-1,3-thiazol-5- 7.90 (m, 2H), 7.51-7.42 (m,6H), 7.31-7.24 yl)phenyl]methyl]carbamoyl) (m, 1H), 7.13-7.08 (m, 7H),7.04-6.93 (m, pyrrolidin-1-yl]-3,3-dimethyl-1- 1H), 6.82-6.74(m, 1H),5.15 (dd, J = 10.7, 2.9 oxobutan-2- Hz, 1H), 4.76-4.57 (m, 1H),4.58-4.52 (m, yl]carbamoyl]butyl)phenyl]methyl] 1H), 4.49-4.39 (m, 2H),4.38-4.31 (m, 1H), carbamoyl)propyl]carbamoyl]- 4.27-4.14 (m, 4H),3.66-3.61 (m, 2H), 3.48- 12-oxo-1- 3.42 (m, 4H), 3.27-3.04 (m, 4H),3.02-2.96 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m,1H), 2.45 (s, 3H), 2.30-2.22 (m, 2H), 2.20-4(13),5,7-trien-11-yl]carbamoyl]- 2.02 (m, 4H), 1.96-1.84 (m, 2H),1.77-1.74 1H-indole-5- (m, 1H), 1.53-1.48 (m, 4H), 1.22-1.19 (m,carbonylphosphonate 1H), 0.94 (s, 9H) 124 I-140 diammonium 2-(2S,11S)-2-[(M − 1)]⁻ = (400 MHz, DMSO-d₆) δ 12.01-11.94 (m, 1H),[(1S)-3-carbamoyl-1-([[4-(5- 1239.50 9.02-8.96 (m, 2H), 8.92-8.86 (m,1H), 8.63- [[(2S)-1-[(2S,4R)-4-hydroxy-2- 8.56 (m, 1H), 8.41-8.33 (m,1H), 8.26 (d, ([[4-(4-methyl-1,3-thiazol-5- J = 7.8 Hz, 1H), 8.01-7.94(m, 1H), 7.89-7.84 yl)phenyl]methyl]carbamoyl) (m, 1H), 7.49-7.36 (m,6H), 7.32-7.25 (m, pyrrolidin-1-yl]-3,3-dimethyl-1- 1H) 7.13-7.06 (m,6H), 7.02-6.98 (m, 1H), oxobutan-2- 6.83-6.78 (m, 1H), 5.15 (dd, J =10.7, 2.9 Hz yl]carbamoyl]pentyl)phenyl]methyl] 1H) 4.72-4.64 (m, 1H),4.58-4.51 (m, 1H), carbamoyl)propyl]carbamoyl]- 4.46-4.42 (m, 2H),4.38-4.31 (m, 1H), 4.24- 12-oxo-1- 4.20 (m, 4H), 3.68-3.63 (m, 3H),3.20-3.18 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m,2H), 3.16-3.11 (m, 2H), 2.98-2.95 (m, 2H),4(13),5,7-trien-11-yl]carbamoyl]- 2.45 (s, 3H), 2.28-2.23 (m, 3H),2.15-2.03 1H-indole-5- (m, 4H), 1.93-1.80 (m, 2H), 1.79-1.77 (m, 2H),carbonylphosphonate 1.54-1.48 (m, 4H), 1.26-1.24 (m, 2H), 0.94 (s, 9H)125 I-141 diammonium 2-[[(2S,11S)-2- 1228.65 (400 MHz, DMSO-d₆) δ12.02-11.96 (m, 1H), [[(2S)-4-carbamoyl-1-[[4-(4- 9.19-8.57 (m, 2H),8.45-8.40 (m, 1H), 8.07- [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.75 (m, 3H),7.59-7.28 (m, 7H), 7.25-6.85 [[(1S)-1-[4-(4-methyl-1,3-thiazol- (m, 7H),6.79-6.49 (m, 2H), 5.32-4.76 (m, 5- 3H), 4.69-4.61 (m, 1H), 4.55-4.48(m, 1H), yl)phenyl]ethyl]carbamoyl] 4.46-4.12 (m, 5H), 3.91-3.74 (m,2H), 3.63- pyrrolidin-l-yl]-3,3-dimethyl-1- 3.58 (m, 3H), 3.33-3.04 (m,4H), 3.01-2.78 oxobutan-2- (m, 1H), 2.58-2.53 (m, 2H), 2.45 (s, 3H),2.35- yl]carbamoyl]butyl)phenyl] 2.20 (m, 2H), 2.18-1.94 (m, 5H),1.86-1.68- methoxy]butan-2-yl]carbamoyl]-12- (m, 2H), 1.63-1.43 (m, 5H),1.37 (d, J = 7.0 oxo-1- Hz, 3H), 0.93 (s, 9H)azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]- 1H-indole-5-carbonylphosphonate. 126I-142 diammonium [3-[(1E)-1- 1251.65 (400 MHz, DMSO-d₆) δ 9.00-8.99 (m,1H), [[(2S,11S)-2-[[(3S,4R)-1- 8.59-8.55 (m, 2H), 7.92-7.87 (m, 2H),7.76- carbamoyl-4-[[4-(4-[[(2S)-1- 7.71 (m, 1H), 7.58-7.52 (m, 2H),7.47-7.33 (m, (2S,4R)-4-hydroxy-2-([[4-(4- 6H), 7.27-7.02 (m, 5H),6.98-6.66 (m, 1H), methyl-1,3-thiazol-5- 6.74-6.72 (m, 1H), 6.47-6.45(m, 1H), 5.20- yl)phenyl]methyl]carbamoyl) 4.98 (m, 2H), 4.59-4.52 (m,1H), 4.51-4.28 pyrrolidin-1-yl]-3,3-dimethyl-1- (m, 6H), 4.25-4.19 (m,1H), 3.81-3.78 (m, 2H), oxobutan-2- 3.71-3.60 (m, 3H), 3.19-2.98 (m,2H), 2.89- yl]carbamoyl]butyl)phenyl]methoxy] 2.82 (m, 1H), 2.52-2.48(m, 4H), 2.44 (s, 3H), pentan-3-yl]carbamoyl]-12-oxo-1- 2.37-2.27 (m,2H), 2.20-1.99 (m, 8H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 1.91-1.89 (m, 1H), 1.78-1.76 (m, 2H), 1.55-4(13),5,7-trien-11- 1.48 (m, 6H), 1.07 (d, J = 6.1Hz, 3H), 0.94 (s,yl]carbamoyl]prop-1-en-2- 9H) yl]phenyl]difluoromethylphosphonate 127I-143 [3-[(1E)-1-[[(8S,10aR)-8-[[(1S)- 1164.85 (400 MHz, DMSO-d₆) δ11.15-11.04 (m, 1H), 3-carbamoyl-1- 8.82-8.72 (m, 1H), 8.52-8.00 (m,2H), 7.71- (diphenylmethylcarbamoyl) 7.56 (m, 2H), 7.56-7.49 (m, 1H),7.44 (d, propyl]carbamoyl]-3-[7-[1-(2,6- J = 6.3 Hz, 1H), 7.36-7.10 (m,11H), 7.06- dioxopiperidin-3-yl)-3-methyl-2- 6.38 (m, 4H), 6.11-6.06 (d,J = 8.5 Hz, 1H), oxo-1,3-benzodiazol-5- 5.62-5.23 (m, 2H), 4.83-4.56 (m,1H), 4.43- yl]heptanoyl]-6-oxo- 4.36 (m, 2H), 4.17-4.02 (m, 1H),3.87-3.71 (m, octahydropyrrolo[1,2- 2H), 3.34 (s, 3H), 3.27-2.99 (m,1H), 2.99- a][1,5]diazocin-5- 2.82 (m, 2H), 2.76-2.56 (m, 5H), 2.46 (m,2 yl]carbamoyl]prop-1-en-2- H), 2.38-2.31 (m, 1H), 2.21-2.04 (m, 4H),yl]phenyl]difluoromethylphosphonic 2.03-1.85 (m, 4H), 1.83-1.66 (m, 3H),1.66- acid 1.40 (m, 6H), 1.40-1.15 (m, 5H) 128 I-144 diammonium[3-[(1E)-1- 1265.70 (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.55[[(2S,11S)-2-[[(3S,4R)-1- (d, J = 7.7 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H),carbamoyl-4-[[4-(4-[[(2S)-1- 7.88-7.84 (m, 2H), 7.73 (s, 1H), 7.57-7.53[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4- (m, 2H), 7.45-7.37 (m, 5H), 7.21-7.16(m, 3H), (4-methyl-1,3-thiazol-5- 7.13-7.05 (m, 4H), 7.01-6.96 (m, 1H),6.75 yl)phenyl]ethyl]carbamoyl] (s, 1H), 6.46 (s, 1H), 5.10-5.08 (m,1H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.94-4.92 (m, 1H), 4.53-4.45 (m,5H), 4.30-4.26 oxobutan-2- (m, 1H), 3.86-3.84(m, 1H), 3.62-3.58 (m,yl]carbamoyl]butyl)phenyl] 3H), 3.32-3.30 (m, 3H), 3.20-3.10 (m, 4H),methoxy]pentan-3-yl]carbamoyl]-12- 2.92-2.89 (m, 1H), 2.56-2.49 (m, 3H),2.46 oxo-1- (s, 3H), 2.32-2.28 (m, 1H), 2.17-1.98 (m, 7H),azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1.81-1.78 (m,2H), 1.62-1.42 (m, 5H), 1.38 4(13),5,7-trien-11- (d, J = 7.0 Hz, 3H),1.18 (d, J = 6.1 Hz, 3H), yl]carbamoyl]prop-1-en-2- 0.93 (s, 9H)yl]phenyl]difluoromethylphosphonate 129 I-1502-[[(5S,8S,10aR)-8-[[(1S)-3- 1155.35 (400 MHz, DMSO-d₆) δ 12.19-12.01(m, 1H), carbamoyl-1- 8.82-8.75 (m, 2H), 8.41 (s, 1H), 8.29-8.13(diphenylmethylcarbamoyl) (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.48 (d, J= propyl]carbamoyl]-3-[7-[3-methyl-1- 8.8 Hz, 1H), 7.44-7.18 (m, 14H),7.07-6.93 (1-methyl-2,6-dioxopiperidin-3- (m, 2H), 6.90-6.68 (m, 2H),6.14-6.08 (m, yl)-2-oxo-1,3-benzodiazol-5- 1H), 5.40 (dd, J = 12.7, 5.2Hz, 1H), 4.99-4.84 yl]heptanoyl]-6-oxo- (m, 1H), 4.48-4.35 (m, 2H),4.22-4.18 (m, octahydropyrrolo[1,2- 1H), 4.08-3.86 (m, 1H), 3.85-3.76(m, 1H), a][1,5]diazocin-5-yl]carbamoyl]- 3.32 (s, 3H), 3.30-3.09 (m,5H), 3.04 (s, 3H), 1H-indole-5- 3.00-2.90 (m, 1H), 2.84-2.57 (m, 4H),2.45- carbonylphosphonic acid 2.30 (m, 1H), 2.25-1.85 (m, 4H), 1.85-1.73(m, 1H), 1.70-1.47 (m, 6H), 1.43-1.32 (m, 6H) 130 I-1572-[[(5S,8S,10aR)-8-[[(1S)-3- [(M − 1)]⁻ = (400 MHz, DMSO-d₆) δ12.15-11.90 (m, 1H), carbamoyl-1- 1167.75 11.09 (s, 2H), 8.94 (s, 1H),8.85-8.66 (m, (diphenylmethylcarbamoyl) 7.15-6.96 (m, 2H), 6.15-6.09 (m,1H), 5.42- propyl]carbamoyl]-3-[2-(4-[[1-(2,6- 5.36 (m, 1H), 5.05-4.96(m, 1H), 4.48-4.34 dioxopiperidin-3-yl)-3-methyl-2- (m, 5H), 4.28-4.18(m, 4H), 3.10-2.81 (m, 5H), oxo-1,3-benzodiazol-5- 2.78-2.53 (m, 7H),2.23-1.87 (m, 9H), 1.85- yl]methyl]piperazin-l-yl)acetyl]-6-oxo-octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5- carbonylphosphonic acid 131 I-1672-[[(5S,8S,10aR)-8-[[(1S)-3- 1182.40 (400 MHz, DMSO-d₆) δ 12.12-11.90(m, 1H), carbamoyl-1- 11.08 (s, 1H), 8.93 - 8.69 (m, 2H), 8.47-8.39(diphenylmethylcarbamoyl) (m, 1H), 8.24-8.14 (m, 1H), 8.01-7.93 (m,propyl]carbamoyl]-6-oxo-3-[3-(1r ,4r)- 1H), 7.52-7.45 (m, 1H), 7.44-7.19(m, 12H), 4-[[1-(2,6-dioxopiperidin-3-yl)-3- 7.04-6.93 (m, 2H),6.84-6.75 (m, 1H), 6.14- methyl-2-oxo-1,3-benzodiazol-5- 6.05 (m, 1H),5.38-5.30 (m, 1H), 5.03-4.86 yl]methyl]cyclohexyl]propanoyl]- (m, 1H),4.49-4.28 (m, 3H), 4.23-4.14 (m, octahydropyrrolo[1,2- 1H), 3.99-3.82(m, 2H), 3.81-3.69 (m, 1H), a][1,5]diazocin-5-yl]carbamoyl]- 2.99-2.83(m, 2H), 2.78-2.59 (m, 4H), 2.25- 1H-indole-5-carbonylphosphonic 1.87(m, 8H), 1.85-1.72 (m, 5H), 1.70-1.38 acid (m, 8H), 1.37-1.31 (m, 2H),1.30-1.11 (m, 3H), 1.05-0.78 (m, 4H) 132 I-1682-[[(5S,8S,10aR)-8-[[(1S)-3- 1183.65 (400 MHz, DMSO-d₆) δ 11.79 (s, 1H),11.05 carbamoyl-1- (s, 1H), 9.91-9.71 (m, 1H), 9.49-9.25 (m, 1H),(diphenylmethylcarbamoyl) 8.61-8.42 (m, 1H), 8.27-8.16 (m, 1H), 7.89-propyl]carbamoyl]-3-(4-[4-[1-(2,6- 7.70 (m, 2H), 7.55-7.08 (m, 12H),6.99- dioxopiperidin-3-yl)-3-methyl-2- 6.88 (m, 2H), 6.73-6.61 (m, 1H),6.13-6.05 (m, oxo-1,3-benzodiazol-5- 1H), 5.32-5.23 (m, 1H), 5.10-5.01(m, 1H), yl]piperazin-1-yl]butanoyl)-6- 4.36-4.20 (m, 3H), 4.13-4.00 (m,1H), 3.94- oxo-octahydropyrrolo[1,2- 3.58 (m, 5H), 3.24-2.98 (m, 7H),2.95-2.78 a][1,5]diazocin-5-yl]carbamoyl]- (m, 3H), 2.72-2.56 (m,4H),2.39-2.24 (m, 2H), 1H-indole-5-carbonylphosphonic 2.18-1.90 (m, 9H),1.78-1.58 (m, 4H), 1.53- acid 1.32 (m, 2H), 1.26-1.21 (m, 1H) 133 I-1752-[[(5S,8S,10aR)-8-[[(1S)-3- 1170.10 (400 MHz, DMSO-d₆) δ 11.97 (s, 1H),11.07 carbamoyl-1- (s, 1H), 9.26-8.61 (m, 3H), 8.21-8.15 (m, 1H),(diphenylmethylcarbamoyl) H), 7.92-7.86 (m, 1H), 7.48-7.22 (m, 13H),propyl]carbamoyl]-3-(3-[4-[1-(2,6- 6.99-6.70 (m, 3H), 6.62 (s, 1H), 6.11(d, J = dioxopiperidin-3-yl)-3-methyl-2- 8.4 Hz, 1H), 5.33-5.28 (m, 1H),5.11-4.91 oxo-1,3-benzodiazol-5- (m, 2H), 4.44-4.32 (m, 3H), 4.00-3.67(m, 4H), yl]piperazin-1-yl]propanoyl)-6- 3.30 (s, 3H), 3.16-3.03 (m,6H), 2.95-2.86 oxo-octahydropyrrolo[1,2- (m, 3H), 2.80-2.56 (m, 6H),2.27-1.84 (m, 7H), a][1,5]diazocin-5-yl]carbamoyl]- 1.74-1.66 (m, 5H).1H-indole-5-carbonylphosphonic acid

The following compounds in Table 74 were synthesized according to theprocedure of Example 1 but using2-(2,3,4,5,6-pentafluorophenoxycarbonyl)-1H-indole-5-carbonylphosphonicacid (Intermediate M3) instead of(2-((4-nitrophenoxy)carbonyl)-1H-indole-5-carbonyl)phosphonic acid(Intermediate M) and corresponding substrates.

TABLE 74 Characterization Data for Exemplary STAT3 Degraders 134 I-1282-[[(5S,8S,10aR)-8-[[(1S)-3- 1182.35 (400 MHz, DMSO-d₆) δ 12.18-11.98(m, 1H), carbamoyl-1- 11.09-11.1 (m, 1H), 8.85-8.74 (m, 2H), 8.48-8.42(diphenylmethylcarbamoyl) (m, 1H), 8.29-8.11 (m, 1H), 7.96 (d, J = 8.8Hz, propyl]carbamoyl]-3-(4-[1-[1- 1H), 7.60-7.14 (m, 13H), 6.98-6.89 (m,1H), 6.8 (2,6-dioxopiperidin-3-yl)-3- 7-6.80 (m, 2H), 6.66-6.59 (m, 1H),6.10 (d, J = 7.2 methyl-2-oxo-1,3- Hz 1H), 5.08 (dd, J = 10.7, 2.9 Hz,1H), 5.04- benzodiazol-5-yl]piperidin-4- 4.94 (m, 1H), 4.50-4.42 (m,1H), 4.40-4.16 (m, yl]butanoyl)-6-oxo- 2H), 3.98-3.92 (m, 2H), 3.84-3.75(m, 2H), 3.58- octahydropyrrolo[1,2- 3.51 (m, 4H), 3.36 (s, 3H),2.96-2.83 (m, 2H), a][1,5]diazocin-5- 2.68-2.61 (m, 4H), 2.22-2.05 (m,3H), 1.98-1.93 yl]carbamoyl]-1H-indole-5- (m, 4H), 1.80-1.74 (m, 8H),1.36-1.28 (m, 6H) carbonylphosphonic acid 135 I-1322-[[(5S,8S,10aR)-8-[[(1S)-3- 1142.55 (400 MHz, DMSO-d₆) δ 12.20-12.01(m, 1H), carbamoyl-1- 11.04 (s, 1H), 8.92-8.70 (m, 2H), 8.43 (d, J =(diphenylmethylcarbamoyl) 6.5 Hz, 1H), 8.25-8.14 (m, 1H), 7.96 (d, J =8.8 Hz, propyl]carbamoyl]-3-(6-[[1- 1H), 7.51 (d, J = 8.7 Hz, 1H),7.47-7.18 (m, (2,6-dioxopiperidin-3-yl)-3- 14H), 6.87-6.60 (m, 2H), 6.41(s, 1H), 6.30 (d, methyl-2-oxo-1,3- J = 8.5 Hz, 1H), 6.12-6.09 (m, 1H),5.33-5.17 (m, benzodiazol-5- 1H), 4.97-4.86 (m, 1H), 4.51-4.14 (m, 3H),3.96- yl]amino]hexanoyl)-6-oxo- 3.92 (m, 1H), 3.83-3.75 (m, 1H),3.27-3.13 (m, octahydropyrrolo 3H), 3.12-2.96 (m, 3H), 2.93-2.85 (m,2H), 2.73- [1,2-a][1,5]diazocin-5- 2.56 (m, 2H), 2.20-2.07 (m, 3H),2.03-1.85 (m, yl]carbamoyl]-1H-indole-5- 4H), 1.82-1.72 (m, 4H),1.68-1.56 (m, 6H), 1.47- carbonylphosphonic acid 1.42 (m, 2H), 1.25-1.17(m, 1H). 136 I-134 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1141.65 (400 MHz,DMSO-d₆) δ 12.27-11.98 (m, 1H), carbamoyl-1- 11.08 (s, 1H), 8.81-8.76(m, 2H), 8.43 (d, J = 6.9 (diphenylmethylcarbamoyl) Hz, 1H), 8.26-8.19(m, 1H), 7.97-7.93 (m, 1H), propyl]carbamoyl]-3-[7-[3-(2,6- 7.57-7.39(m, 2H), 7.38-7.20 (m, 11H), 7.09-6.96 dioxopiperidin-3-yl)-1- (m, 2H),6.93-6.86 (m, 1H), 6.81-6.67 (m, 1H), methyl-2-oxo-1,3- 6.12-6.10 (m,1H), 5.41-5.29 (m, 1H), 5.04-4.92 benzodiazol-5-yl]heptanoyl]- (m, 1H)4.49-4.44 (m, 1H), 4.42-4.35 (m, 2H), 6-oxo-octahydropyrrolo[1,2-4.21-4.15 (m, 1H), 3.96-3.77 (m, 4H), 3.30 (s, a][1,5]diazocin-5- 3H),3.14-3.07 (m, 1H), 2.94-2.84 (m, 1H), 2.81- yl]carbamoyl]-1H-indole-5-2.70 (m, 1H), 2.67-2.61 (m, 1H), 2.60-2.56 (m, carbonylphosphonic acid2H), 2.39-2.34 (m, 1H), 2.20-2.13 (m, 1H), 2.13- 2.04 (m, 2H), 2.03-1.96(m, 2H), 1.94-1.85 (m, 2H), 1.83-1.70 (m, 3H), 1.68-1.64 (m, 1H), 1.59-1.53 (m, 4H), 1.38-1.32 (m, 4H), 1.21-1.16 (m, 1H) 137 I-1352-[[(5S,8S,10aR)-8-[[(1S)-3- 1154.35 (400 MHz, DMSO-d₆) δ 12.14 (s, 1H),11.06 (s, carbamoyl-1- 1H), 8.82-8.78 (m 2H), 8.46 (d, J = 7.0 Hz, 1H),(diphenylmethylcarbamoyl) 8.26-8.18 (m, 1H), 7.97-7.93 (m, 1H),7.55-7.51 propyl]carbamoyl]-3-(4-[1-[1- (m, 1H), 7.47-7.39 (m, 1H),7.37-7.21 (m, 12H), (2,6-dioxopiperidin-3-yl)-3- 6.94-6.83 (m, 1H), 6.80(s, 1H), 6.30 (s, 1H), methyl-2-oxo-1,3- 6.12-6.08 (m, 2H), 5.31-5.23(m, 1H), 5.00-4.90 benzodiazol-5-yl]azetidin-3- (m, 1H), 4.47-4.43 (m,1H), 4.42-4.28 (m, 2H), yl]butanoyl)-6-oxo- 4.26-4.17 (m, 1H), 3.99-3.88(m, 4H), 3.85-3.73 octahydropyrrolo[1,2- (m, 3H), 3.26 (s, 3H),2.91-2.87 (m, 1H), 2.72- a][1,5]diazocin-5- 2.64 (m, 3H), 2.22-2.06 (m,4H), 2.03-1.89 (m, yl]carbamoyl]-1H-indole-5- 4H), 1.86-1.72 (m, 4H),1.65-1.59 (m, 6H) carbonylphosphonic acid 138 I-1452-[[(2S,11S)-2-[[(3S,4R)-1- 1262.95 (400 MHz, CD₃OD) 8.98 (d, J = 1.4Hz, 1H), carbamoyl-4-[[3'-([[(2S)-1- 8.89 (s, 1H), 8.66 (t, J J = 6.0Hz, 1H) 8.11-8.09 [(2S,4R)-4-hydroxy-2-([[4-(4- (m, 1H), 8.02 (d, J J =9.4 Hz, 1H), 7.95 (d, J = methyl-1,3-thiazol-5- 9.1 Hz, 1H), 7.61-7.54(m, 3H), 7.51-7.46 (m, yl)phenyl]methyl]carbamoyl) 3H), 7.42-7.35 (m,4H), 7.30 (d, J = 7.7 Hz, 1H), pyrrolidin-1-yl]-3,3-dimethyl- 7.11 (d, J= 3.2 Hz, 1H), 7.02-7.00 (m, 2H), 5.18- 1-oxobutan-2- 5.16 (m, 1H),4.82-4.76 (m, 2H), 4.66 (d, J = 9.0 yl]carbamoyl]methyl)-[1,1'- Hz, 1H),4.61-4.52 (m, 5H), 4.45-4.36 (m, 1H), biphenyl]-4- 4.05-4.03 (m, 1H),3.91 (d, J = 11.0 Hz, 1H), yl]methoxy]pentan-3- 3.80 (dd, J = 10.9, 3.9Hz, 1H), 3.75-3.66 (m, 2H), yl]carbamoyl]-12-oxo-1- 3.65-3.60 (m, 1H),3.52-3.47 (m, 1H), 3.25-3.22 azatricyclo[6.4.1.0{circumflex over( )}[4,13]] (m, 1H), 3.05-2.98 (m, 1H), 2.48 (s, 3H), 2.45-trideca-4(13),5,7-trien-11- 2.17 (m, 5H), 2.13-1.97 (m, 2H), 1.74-1.72(m, 1 yl]carbamoyl]-1H-indole-5- H), 1.23 (d, J = 6.4 Hz, 3H), 1.03 (s,9H) carbonylphosphonic acid 139 I-146 diammonium 2-[[(2S,11S)-2- 1240.07(400 MHz, CD₃OD) 9.00-8.95 (m, 1H), 8.89 (s,[[(3S,4R)-1-carbamoyl-4-[(4- 1H), 8.11 (dd, J = 8.8, 1.6 Hz, 1H), 8.03(d, J = [[(1r,3r)-3-[[(2S)-1-[(2S,4R)- 9.3 Hz, 1H), 7.52 (d, J = 8.8 Hz,1H), 7.51-7.45 4-hydroxy-2-([[4-(4-methyl- (m, 2H), 7.45-7.38 (m, 2H),7.38 (d, J = 0.9 Hz, 1,3-thiazol-5- 1H), 7.22 (d, J = 7.8 Hz, 2H),7.14-7.06 (m, 4H), yl)phenyl]methyl]carbamoyl) 5.20-5.18 (m, 1H),4.83-4.76 (m, 1H), 4.69-4.59 pyrrolidin-1-yl]-3,3-dimethyl- (m, 1H),4.58 (d, J = 7.1 Hz, 1H), 4.52-4.45 (m, 1-oxobutan-2- 3H), 4.36 (d, J =15.5 Hz, 1H), 4.01 (d, J = 11.1 yl]carbamoyl]cyclobutyl] Hz, 1H), 3.94(d, J = 11.0 Hz, 1H), 3.83 (dd, J = methyl]phenyl)methoxy]pentan- 11.0,3.8 Hz, 1H), 3.66-3.40 (m, 3H), 3.24 (d, 3-yl]carbamoyl]-12-oxo-1- J =5.2 Hz, 2H), 3.12-2.97 (m, 2H), 2.68-2.62 (m,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 2H), 2.49 (s, 3H),2.45-2.20 (m, 7H), 2.20-1.85 trideca-4(13),5,7-trien-11- (m, 5H),1.71-1.69 (m, 1H), 1.20 (d, J = 6.3 Hz, yl]carbamoyl]-1H-indole-5- 3H),1.04 (s, 9H) carbonylphosphonate 140 I-147 2-[[(5S,8S,10aR)-8-[[(1S)-3-1354.53 (400 MHz, DMSO-d₆) δ 12.18-12.01 (m, 1H), carbamoyl-1- 8.99 (s,1H), 8.8.-8.76 (m, 2H), 8.58-8.56 (m, 1H), (diphenylmethylcarbamoyl)8.42 (d, J = 6.7 Hz, 1H), 8.27-8.13 (m, 1H), 7.97propyl]carbamoyl]-3-(8-[[(2S)- (d, J = 8.8 Hz, 1H), 7.84-7.81 (m, 1H),7.53 (d, 1-[(2S,4R)-4-hydroxy-2-(4- J = 8.7 Hz, 1H), 7.44-7.35 (m, 8H),7.31-7.27 (4-methyl-1,3-thiazol-5- (m, 8H), 6.80-6.70 (m, 1H), 6.11 (dd,J = 8.5, yl)phenyl]methyl]carbamoyl) 4.7 Hz, 1H), 5.00-4.95 (m, 2H),4.59-4.52 (m, 1H), pyrrolidin-1-yl]-3,3-dimethyl- 4.48-4.34 (m, 5H),4.28-4.18 (m, 2H), 3.97-3.90 1-oxobutan-2- (m, 1H), 3.81-3.76 (m, 1H),3.69-3.64 (m, 4H), yl]carbamoyl]octanoyl)-6- 3.32-3.27 (m, 4H),2.94-2.57 (m, 1H), 2.45 (s, 3 oxo-octahydropyrrolo[1,2- H), 2.33-2.21(m, 1H), 2.15-2.11 (m, 5H), 2.06- a][1,5]diazocin-5- 1.99 (m, 2H),1.94-1.87 (m, 2H), 1.85-1.61 (m, 1 yl]carbamoyl]-1H-indole-5- H),1.56-1.52 (m, 1H), 1.32-1.27 (m, 11H), 0.94 carbonylphosphonic acid (s,9H). 141 I-148 2-[[(5S,8S,10aR)-8-[[(1S)-3- [(M − (400 MHz, DMSO-d₆)δ12.08-11.91 (m, 1H), carbamoyl-1- 1)]⁻ = 8.98 (s, 1H), 8.87-8.76 (m,2H), 8.61-8.55 (m, 1H), (diphenylmethylcarbamoyl) 1381.65 8.27-8.13 (m,1H), 7.98 (d, J = 8.8 Hz, 1H), 7.84 propyl]carbamoyl]-3-(10- (d, J = 9.3Hz, 1H), 7.50-7.18 (m, 17H), 6.81- [[(2 S)-1-[(2S,4R)-4-hydroxy- 6.53(m, 1H), 6.14-6.06 (m, 1H), 5.15-4.87 (m, 22-([[4-(4-methyl-1,3-thiazol- H), 4.58-4.17 (m, 9H), 3.96-3.72 (m, 2H),3.68- 5- 3.63 (m, 3H), 3.25-2.18 (m, 2H), 2.62-2.59 (m, 2yl)phenyl]methyl]carbamoyl) H), 2.45 (s, 3H), 2.20-2.16 (m, 1H),2.13-2.08 pyrrolidin-1-yl]-3,3-dimethyl- (m, 9H), 1.93-1.89 (m, 4H),1.53-1.49 (m, 5H), 1-oxobutan-2- 1.32-1.25 (m, 10H), 0.94 (s, 9H)yl]carbamoyl]decanoyl)-6- oxo-octahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5- carbonylphosphonic acid 142 I-149 diammonium2-[[(2S,11S)-2- 1243.70 (400 MHz, DMSO-d₆) δ 11.98-11.90 (m, 1H),[[(3S,4R)-1-carbamoyl-4-[[4-( 9.04-8.87 (m, 3H), 8.34 (d, J = 7.9 Hz,1H), 7.97 4-[[(2S)-1-[(2S,4S)-4-hydroxy- (dd, J = 8.6, 1.5 Hz, 1H), 7.89(t, J = 8.9 Hz, 2H), 2-[[(1S)-1-[4-(4-methyl-1,3- 7.46-7.39 (m, 7H),7.34-7.14 (m, 4H), 7.14-6.92 thiazol-5-yl)phenyl]ethyl] (m, 5H), 6.70(s, 1H), 5.13 (dd, J = 10.6, 3.0 Hz, carbamoyl]pyrrolidin-1-yl]-3,3-1H), 4.96-4.91 (m, 1H), 4.71-4.66 (m, 1H), 4.49-dimethyl-1-oxobutan-2-yl] 4.29 (m, 4H), 4.22-4.17 (m, 1H) 3.94-3.89 (m,carbamoyl]butyl)phenyl]methoxy] 1H), 3.84-3.78(m, 1H), 3.53-3.42,(m,3H), 3.41- pentan-3-yl]carbamoyl]-12- 3.37 (m, 2H), 3.30-3.04 (m, 2H),2.93-2.88 (m, oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}[4, 1H),2.47 (s, 3H), 2.35-2.24 (m, 4H), 2.20-1.9413]]trideca-4(13),5,7-trien-11- (m, 4H), 1.86-1.72 (m, 1H), 1.69-1.63(m, 1H), yl]carbamoyl]-1H-indole-5- 1.57-1.45 (m, 5H), 1.39 (d, J = 6.9Hz, 3H), 1.08 carbonylphosphonate (d, J = 6.2 Hz, 3H), 0.96 (s, 9H) 143I-151 2-[[(2S,11S)-2-[[(3S,4R)-1- 1229.45 (400 MHz, DMSO-d₆) δ 12.06 (s,1H), 8.99-8.97 carbamoyl-4-([4-[3-([[(2S)-1- (m, 2H), 8.84 (s, 1H), 8.58(t, J = 6.1 Hz, 1H), [(2S,4R)-4-hydroxy-2-([[4-(4- 7.95 (d, J = 8.7 Hz,1H), 7.89 (d, J = 9.0 Hz, 1H), methyl-1,3-thiazol-5-yl)phenyl] 7.56-7.37(m, 6H), 7.19-7.17 (m, 3H), 7.13-7.06 methyl]carbamoyl)pyrrolidin- (m,4H), 7.01 (t, J = 7.4 Hz, 1H), 6.69 (s, 1H),1-yl]-3,3-dimethyl-1-oxobutan- 6.24-6.13 (m, 2H), 5.16-5.09 (m, 1H),4.71-4.66 2-yl]carbamoyl]amino) (m, 1H), 4.49-4.33 (m, 7H), 4.27-4.20(m, 1H), propyl]phenyl]methoxy)pentan- 3.82-3.79 (m, 2H), 3.69-3.64 (m,1H), 3.53-3.50 3-yl]carbamoyl]-12-oxo-1- (m, 1H), 3.49-3.42 (m, 3H),3.25-3.17 (m, 1H), azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 3.18-3.10 (m, 2H), 3.07-2.90 (m, 3H), 2.57-2.554(13),5,7-trien-11-yl]carbamoyl]- (m, 1H), 2.45 (s, 3H), 2.26-2.22 (m,2H), 2.10- 1H-indole-5-carbonylphosphonic 2.00 (m, 3H), 1.96-1.85 (m,1H), 1.83-1.72 (m, 1H), acid 1.67-1.52 (m, 3H), 1.08 (d, J = 6.2 Hz,3H), 0.93 (s, 9H) 144 I-152 2-[[(2S,11S)-2-[[(2S)-4- 1215.20 (400 MHz,DMSO-d₆) δ 12.07 (s, 1H), 9.00-8.98 carbamoyl-1-[4-(5-[[(2S)-1-[(2S,4R)-(m, 2H), 8.83 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.114-hydroxy-2-([[4-(4-methyl- (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.8 Hz,1H), 1,3-thiazol-5-yl)phenyl]methyl] 7.84 (d, J = 9.3 Hz, 1H), 7.58-7.34(m, 6H), 7.25 carbamoyl)pyrrolidin-1-yl]- (s, 1H), 7.10-7.07 (m, 4H),6.99 (t, J = 8.3 Hz, 3,3-dimethyl-1-oxobutan-2-yl] 1H), 6.81 (d, J = 8.3Hz, 2H), 6.74 (s, 1H), 5.08 carbamoyl]pentyl)phenoxy] (dd J = 10.7, 2.9Hz, 1H), 4.71-4.67 (m, 1H), 4.54 butan-2-yl]carbamoyl]-12- (d, J = 9.3Hz, 1H), 4.49-4.38 (m, 2H), 4.38-4.34 oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] (m, 1H), 4.25-4.20 (m, 1H),4.02-3.94 (m, trideca-4(13),5,7-trien-11-yl] 1H), 3.92-3.82 (m, 2H),3.70-3.63 (m, 3H), 3.27-3.04 carbamoyl]-1H-indole-5-carb (m, 4H),2.89-2.84 (m, 1H), 2.48-2.46 (m, onylphosphonic acid 1H), 2.45 (s, 3H),2.36-2.16 (m, 3H), 2.17-1.95 (m, 4H), 1.94-1.79 (m, 2H), 1.77-1.59 (m,1H), 1.57-1.46 (m, 5H), 1.28-1.20 (m, 3H), 0.93 (s, 9H). 145 I-1532-[[(2S,11S)-2-[[(2S)-4- 1194.50 (400 MHz, DMSO-d₆) δ 12.08 (s, 1H),8.99-8.97 carbamoyl-1-[(9-[[(2S)-1-[(2S,4R)- (m, 2H), 8.83 (s, 1H), 8.57(t, J = 6.1 Hz, 1H), 4-hydroxy-2-([[4-(4-methyl-1,3- 8.04-7.80 (m, 3H),7.56-7.34 (m, 7H), 7.21 (s, 1H), thiazol-5-yl)phenyl]methyl] 7.11-7.09(m, 2H), 7.04-6.93 (m, 1H), 6.71 (s, carbamoyl)pyrrolidin-1-yl]-3,3-1H), 5.09-5.05 (m, 1H), 4.74-4.62 (m, 1H), 4.55dimethyl-1-oxobutan-2-yl] (d, J = 9.4 Hz, 1H), 4.47-4.38 (m, 2H),4.37-4.34 carbamoyl]nonyl)oxy]butan-2- (m, 1H), 4.26-4.20 (m, 1H),3.84-3.73 (m, 1H), yl]carbamoyl]-12-oxo-1- 3.72-3.60 (m, 2H), 3.53-3.44(m, 2H), 3.36-3.24 azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- (m, 3H), 3.24-3.07 (m, 1H), 2.92-1.86 (m, 1H),4(13),5,7-trien-11-yl]carbamoyl]- 2.45 (s, 3H), 2.38-2.17 (m, 3H),2.17-1.97 (m, 4H), 1H-indole-5- 1.95-1.88 (m, 1H), 1.75-1.66 (m, 1H),1.63-1.36 carbonylphosphonic acid (m, 5H), 1.29-1.20 (m, 13H), 0.94 (s,9H) 146 I-154 2-[[(2S,11S)-2-[[(2S)-4-carbamoyl- 1180.70 (400 MHz,DMSO-d₆) δ 12.08 (s, 1H), 9.00-8.96 1-[(8-[[(2S)-1-[(2S,4R)- (m, 2H),8.83 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 4-hydroxy-2-([[4-(4-methyl-1,3-8.01-7.93 (m, 1H), 7.92-7.82 (m, 2H), 7.55-7.51thiazol-5-yl)phenyl]methyl] (m, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.44-7.35(m, 4H), carbamoyl)pyrrolidin-1-yl]-3,3- 7.21 (s, 1H), 7.12-7.09 (m,2H), 7.04-6.95 dimethyl-1-oxobutan-2-yl] (m, 1H), 6.71 (s, 1H),5.12-5.09 (m, 1H), 5.09-5. carbamoyl]octypoxy]butan-2- (m, 1H),4.70-4.66 (m, 1H), 4.57-4.52 (m, 1H), yl]carbamoyl]-12-oxo-1- 4.48-4.40(m, 2H), 4.38-4.34 (m, 1H), 4.23-4.19 azatricyclo[6.4.1.0{circumflexover ( )}[4,13]]trideca- (m, 1H), 3.85-3.74 (m, 1H), 3.71-3.61 (m, 2H),4(13),5,7-trien-11-yl]carbamoyl]- 3.50-3.46 (m, 1H), 3.33-3.28 (m, 3H),3.25-3.10 1H-indole-5-carbonylphosphonic (m, 2H), 2.92-2.87 (m, 1H),2.45 (s, 3H), 2.32- acid 2.17 (m, 3H), 2.14-1.96 (m, 4H), 1.92-1.89 (m,1H), 1.78-1.64 (m, 1H), 1.60-1.33 (m, 6H), 1.32- 1.17 (m, 10H), 0.94 (s,9H) 147 I-155 2-[[(2S,11S)-2-[[(2S)-4- 1166.45 (400 MHz, DMSO-d₆) δ12.05 (s, 1H), 8.91-8.97 carbamoyl-1-[(7-[[(2S)-1-[(2S,4R)- (m, 2H),8.85 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.00-4-hydroxy-2-([[4-(4-methyl-1,3- 7.81 (m, 3H), 7.55-7.35 (m, 6H), 7.21(s, 1H), thiazol-5-yl)phenyl]methyl] 7.12-7.08 (m, 2H), 7.04-6.97 (m,1H), 6.71-6.55 carbamoyl)pyrrolidin-1-yl]-3,3- (m, 1H), 5.11-4.99 (m,1H), 4.72-4.63 (m, 1H), dimethyl-1-oxobutan-2-yl] 4.57-4.53 (m, 1H),4.47-4.40 (m, 2H), 4.37-4.32 carbamoyl]heptypoxy]butan- (m, 1H),4.27-4.19 (m, 1H), 3.81-3.75 (m, 2H), 2-yl]carbamoyl]-12-oxo-1-3.71-3.60 (m, 2H), 3.57-3.43 (m, 2H), 3.26-3.00azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- (m, 2H),2.95-2.83 (m, 1H), 2.69-2.67 (m, 1H), 4(13),5,7-trien-11-yl]carbamoyl]-2.45 (s, 3H), 2.35-2.17 (m, 3H), 2.16-1.97 (m, 1H-indole-5- 4H),1.94-1.87 (m, 1H), 1.78-1.62 (m, 1H), 1.61- carbonylphosphonic acid 1.31(m, 6H), 1.28-1.22 (m, 8H), 1.09-1.02 (m, 1H), 0.96 (s, 9H) 148 I-156diammonium 2-[[(5S,8S,10aR)- 1189.40 (400 MHz, DMSO-d₆) δ 8.89 (s, 1H),8.79-8.61 8-[[(1S)-3-carbamoyl-1- (m, 2H), 8.45-8.35 (m, 1H), 8.31-8.28(m, 1H), (diphenylmethylcarbamoyl)propyl] 8.01-7.93 (m, 1H), 7.41-7.19(m, 16H), 7.23-7.09 carbamoyl]-3-[3-(2-[2-[1-(2, (m, 3H), 7.04-6.93 (m,1H), 6.93-6.87 (m, 1H), 6-dioxopiperidin-3-yl)-3- 6.83-6.68 (m, 1H),6.12-6.09 (m, 1H), 5.37-5.33 methyl-2-oxo-1,3-benzodiazol-5- (m, 1H),4.94-4.89 (m, 1H), 4.45-4.41 (m, 3H), yl]ethyl]phenyl)propanoyl]-6-4.12-3.40 (m, 10H), 3.35-3.25 (m, 3H) 3.05-2.95oxo-octahydropyrrolo[1,2-a] (m, 5H), 2.78-2.68 (m, 3H), 2.15-2.05 (m,3H), [1,5]diazocin-5-yl]carbamoyl]- 2.01-1.82 (m, 4H), 1.75-1.65 (m, 3H)1H-indole-5- carbonylphosphonate 149 I-158 2-[[(5S,8S,10aR)-8-[[(1S)-3-1168.70 (400 MHz, DMSO-d₆) δ 12.38-11.81 (m, 1H), carbamoyl-1- 11.10 (s,1H), 9.33-9.28 (m, 1H), 8.95-8.55 (m, (diphenylmethylcarbamoyl) 3H),8.30-8.26 (m, 1H), 7.96 (d, J = 8.7 Hz, 1H), propyl]carbamoyl]-7.57-7.53 (m, 1H), 7.51-7.40 (m, 1H), 7.38-7.303-[2-(4-[[1-(2,6-dioxopiperidin- (m, 3H), 7.30-7.17 (m, 7H), 7.08-6.98(m, 2H), 3-yl)-3-methyl-2-oxo-1,3- 6.90-6.67 (m, 2H), 6.11-6.07 (m, 1H),5.37-5.33 benzodiazol-5-yl]methyl]piperidin- (m, 1H), 5.24-5.18 (m, 1H),4.51-4.22 (m, 5H), 1-yl)acetyl]-6-oxo- 4.18-3.63 (m, 3H), 3.32 (s, 3H),3.29-3.10 (m, octahydropyrrolo[1,2-a][1,5]diazocin- 3H), 3.06-2.81 (m,3H), 2.74-2.63 (m, 2H), 2.59- 5-yl]carbamoyl]-1H-indole- 2.55 (m, 2H),2.27-1.49 (m, 17H), 1.39-1.04 (m, 5-carbonylphosphonic acid 1H) 150I-159 2-[[(2S,11S)-2-[[(2S)-4-carba 1176.65 (400 MHz, DMSO-d₆) δ12.12-11.96 (m, 1H), moyl-1-[(8-[[(2S)-1-[(2S,4R)- 9.04-8.96 (m, 1H),8.95 (d, J = 8.0 Hz, 1H), 8.93- 4-hydroxy-2-(4-(4-methyl- 8.86 (m, 1H),8.62-8.54 (m, 1H), 8.03-7.94 (m, 1,3-thiazol-5-yl)phenyl]methyl] 2H),7.91-7.86 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H),carbamoyl)pyrrolidin-1-yl]-3,3- 7.46-7.37 (m, 6H), 7.22 (s, 1H),7.13-7.09 (m, dimethyl-1-oxobutan-2-yl] 2H), 7.03-6.97 (m, 1H),6.76-6.68 (m, 1H), 5.08 carbamoyl]oct-2-yn-1-yl)oxy] (dd, J = 10.7, 2.9Hz, 1H), 4.74-4.65 (m, 1H), butan-2-yl]carbamoyl]-12- 4.62-4.54 (m, 1H),4.49-4.39 (m, 2H), 4.41-4.33 oxo-1-azatricyclo[6.4.1.0{circumflex over( )}[4,13]] (m, 1H), 4.27-4.21 (m, 1H), 4.17-4.08 (m, 2H),trideca-4(13),5,7-trien-11-yl] 3.84-3.77 (m, 2H), 3.73-3.62 (m, 2H),3.52-3.48 carbamoyl]-1H-indole-5- (m, 1H), 3.23-3.07 (m, 2H), 2.93-2.86(m, 2H), carbonylphosphonic acid 2.45 (s, 3H), 2.27-2.18 (m, 4H),2.15-1.99 (m, 4H), 1.92-1.90 (m, 1H), 1.75-1.72 (m, 2H), 1.62- 1.38 (m,6H), 1.38-1.15 (m, 4H), 0.95 (s, 9H) 151 I-160 diammonium2-[[(2S,11S)-2- 1284.05 (400 MHz, DMSO-d₆) δ 11.95-11.87 (m, 1H),[[(3S,4R)-1-carbamoyl-4-([4-[ 8.99-8.92 (m, 2H), 8.62-8.54 (m, 1H),8.04-7.91 4-(2-[[(2S)-1-[(2S,4R)-4- (m, 2 H), 7.89-7.84 (m, 1H),7.52-7.35 (m, 6H), hydroxy-2-([[4-(4-methyl-1,3- 7.24-7.04 (m, 4H),7.04-6.96 (m, 3H), 6.85-6.78 thiazol-5-yl)phenyl]methyl] (m, 2H),6.72-6.65 (m, 1H), 5.24-5.03 (m, 2H), carbamoyl)pyrrolidin-1-yl]-3,3-4.74-4.61 (m, 1H), 4.60-4.54 (m, 1H), 4.49-4.39dimethyl-1-oxobutan-2-yl] (m, 4H), 4.38-4.29 (m, 4H), 4.27-4.19 (m, 1H),carbamoyl]ethyl)piperidin-1-yl] 3.79-3.71 (m, 1H), 3.69-3.61 (m, 2H),2.91-2.84 phenyl]methoxy)pentan-3-yl] (m, 1H), 2.70-2.67 (m, 1H), 2.45(s, 3H), 2.38- carbamoyl]-12-oxo-1-azatricyclo 2.30 (m, 2H), 2.29-2.11(m, 4H), 2.13-1.97 (m, [6.4.1.0{circumflex over ( )}4,13]]trideca-4(13),4H), 1.97-1.82 (m, 2H), 1.83-1.62 (m, 4H), 1.61-5,7-trien-11-yl]carbamoyl]-1H- 1.27 (m, 4H), 1.27-1.12 (m, 3H),1.12-1.04 (m, indole-5-carbonylpho sphonate 3H), 0.95 (s, 9H) 152 I-161diammonium 2-[[(2S,11S)-2- 1256.00 (400 MHz, CD₃OD) δ 12.12-11.96 (m,1H), 9.02- [(3S,4R)-1-carbamoyl-4-[[4- 8.96 (m, 2H), 8.55-8.43 (m, 2H),7.94-7.86 (m, (4-[[(2S)-1-[(2S,4R)-4-hydroxy- 3H), 7.49-7.38 (m, 6H),7.29-6.51 (m, 9H), 5.15- 2-([[4-(4-methyl-1,3-thiazol- 5.06 (m, 2H),4.82-4.15 (m, 8H), 3.94-3.82 (m, 5-yl)phenyl]methyl]carbamoyl) 1H), 3.67(m, 4H), 2.94-2.60 (m, 5H), 2.45 (s, pyrrolidin-1-yl]-3,3-dimethyl- 3H),2.36-1.85 (m, 3H), 1.84-1.73 (m, 5H), 1.72- 1-oxobutan-2-yl]carbamoyl]1.62 (m, 4H), 1.44-1.35 (m, 2H), 1.27-1.18 (m,piperidin-1-yl)phenyl]methoxy] 3H), 1.12-1.06 (m, 3H), 0.95 (s, 9H)pentan-3-yl]carbamoyl]- 12-oxo-1-azatricyclo [6.4 .1.0{circumflex over( )} [4,13]]trideca-4(13),5,7-trien- 11-yl]carbamoyl]-1H-indole-5-carbonylphosphonate 153 I-162 diammonium 2-[[(2S,11S)-2- 1269.65 (400MHz, DMSO-d₆) δ 11.98-11.89 (m, 1H), [[(3S,4R)-1-carbamoyl-4-([4-9.02-8.89 (m, 2H), 8.64-8.56 (m, 1H), 8.47-7.53[4-([[(2S)-1-[(2S,4R)-4-hydroxy- (m, 3H), 7.50-7.32 (m, 6H), 7.32-6.90(m, 7H), 2-([[4-(4-methyl-1,3-thiazol- 6.88-6.79 (m, 2H), 6.73-6.66 (m,1H), 5.43-4.97 5-yl)phenyl]methyl]carbamoyl) (m, 2H), 4.71-4.52 (m, 2H),4.48-4.40 (m, 2H), pyrrolidin-1-yl]-3,3-dimethyl- 4.38-4.14 (m, 4H),3.79-3.71 (m, 2H), 3.69-3.56 1-oxobutan-2-yl]carbamoyl] (m, 4H),3.54-3.40(m, 3H), 3.22-3.09 (m, 2H) methyl)piperidin-1-yl]phenyl]2.91-2.87 (m, 1H), 2.71-2.54 (m, 3H), 2.45 (s,methoxy)pentan-3-yl]carbamoyl]- 3H), 2.32-2.25 (m, 4H), 2.18-1.88 (m,6H), 1.83- 12-oxo-1-azatricyclo 1.76 (m, 2H), 1.73-1.43 (m, 4H),1.41-1.15 (m, [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13), 3H),1.09-1.01 (m, 4H), 0.96 (s, 9H) 5,7-trien-11-yl]carbamoyl]-1H-indole-5-carbonylphosphonate 154 I-163 diammonium 2-[[(2S,11S)-2-1255.80 (400 MHz, DMSO-d₆) δ 12.12-11.98 (m, 1H),[(3S,4R)-1-carbamoyl-4-[(4- 9.03-8.96 (m, 2H), 8.85-8.79 (m, 1H),8.56-8.47 [[3-([[(2S)-1 4(2S,4R)-4-hydroxy- (m, 1H), 7.98-7.92 (m, 1H),7.91-7.87 (m, 1H), 2-([[4-(4-methyl-1,3-thiazol- 7.86-7.82 (m, 1H), 7.53(d, J = 8.7 Hz, 1H), 7.50- 5-yl)phenyl]methyl]carbamoyl) 7.46 (m, 1H),7.44-7.36 (m, 4H), 7.20-6.96 (m, pyrrolidin-1-yl]-3,3-dimethyl- 8H),6.73-6.65 (m, 1H), 5.16-5.08 (m, 1H), 4.70- 1-oxobutan-2-yl]carbamoyl]4.65 (m, 1H), 4.57-4.52 (m, 1H), 4.49-4.33 (m, methyl)cyclobutyl]methyl]4H) 4.24-4.20 (m, 1H) 3.83-3.79 (m, 1H) 3.71-phenyl)methoxy]pentan-3-yl] 3.59, (m, 2H), 3.58-3.44 (m, 2H), 3.45-3.41(m, carbamoyl]-12-oxo-1-azatricyclo 4H), 3.28-3.16 (m, 2H), 3.16-3.05(m, 2H), 2.92- [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13), 2.86(m, 1H), 2.69-2.63 (m, 1H), 2.61-2.57 (m, 5,7-trien-11-yl]carbamoyl]-1H), 2.45 (s, 3H), 2.40-2.36 (m, 1H), 2.33-2.151H-indole-5-carbonylphosphonate (m, 4H), 2.11-1.98 (m, 3H), 1.92-1.88(m, 1H), 1.78-1.74 (m, 3H), 1.59-1.55 (m, 1H), 1.44-1.40 (m, 1H),1.12-1.04 (m, 3H), 0.93 (s, 9H) 155 I-1642-[[(2S,11S)-2-[[(2S)-4-carbamoyl- [(M − (400 MHz, DMSO-d₆) δ 11.86 (s,1H), 8.99 (s, 1-[3-(5-[[(2S)-1-[(2S,4R)- 1)]⁻ = 1H), 8.96-8.88 (m, 2H),8.61-8.55 (m, 1H), 8.12- 4-hydroxy-2-([[4-(4-methyl- 1212.35 8.05 (m,1H), 7.98-7.92 (m, 1H), 7.89-7.82 (m, 1,3-thiazol-5-yl)phenyl]methyl]1H), 7.45-7.35 (m, 6H), 7.29-7.22 (m, 2H), 7.20-carbamoyl)pyrrolidin-1-yl]- 7.13 (m, 2H), 7.12-7.06 (m, 2H), 7.05-6.95(m, 3,3-dimethyl-1-oxobutan-2-yl] 1H), 6.79-6.69 (m, 4H), 5.13-5.03 (m,1H), 4.72- carbamoyl]pentyl)phenoxy] 4.65 (m, 1H), 4.58-4.52 (m, 1H),4.48-4.39 (m, butan-2-yl]carbamoyl]-12-oxo- 2H), 4.38-4.32 (m, 1H),4.26-4.19 (m, 1H), 4.03- 1-azatricyclo[6.4.1.0{circumflex over( )}[4,13]] 3.96 (m, 1H), 3.91-3.87 (m, 2H), 3.70-3.60 (m,trideca-4(13),5,7-trien-11-yl] 2H), 3.47-3.41 (m, 3H), 3.16-3.08 (m,2H), 2.92- carbamoyl]-1H-indole-5- 2.84 (m, 1H), 2.45 (s, 3H), 2.35-2.22(m, 3H), carbonylphosphonic acid 2.16-2.01 (m, 4H), 1.95-1.78 (m,2H),1.77-1.65 (m, 2H), 1.59-1.46 (m, 4H), 1.32-1.19 (m, 2H), 0.94 (s,9H). 156 I-165 2-[[(5S,8S,10aR)-3-acetyl-8-[ 1252.50 (400 MHz, DMSO-d₆)δ 12.24-11.96 (m, 1H), [(3S,4R)-1-carbamoyl-4-[[4- 8.99 (s, 1H),8.87-8.79 (m, 1H), 8.61-8.46 (m, (4-[[(2S)-1-[(2S,4R)-4-hydroxy- 2H),7.99-7.94 (m, 1H), 7.92-7.76 (m, 2H), 7.53-2-([[4-(4-methyl-1,3-thiazol- 7.48 (m, 1H), 7.47-7.35 (m, 5H), 7.26-7.20(m, 5-yl)phenyl]methyl]carbamoyl) 2H), 7.20-7.11 (m, 3H), 6.79-6.55 (m,1H), 5.19- pyrrolidin-1-yl]-3,3-dimethyl- 4.95 (m, 2H), 4.61-4.51 (m,1H), 4.48-4.38 (m, 1-oxobutan-2-yl]carbamoyl] 4H), 4.37-4.30 (m, 1H),4.30-4.18 (m, 1H), 3.93- butyl)phenyl]methoxy]pentan- 3.83 (m, 2H),3.80-3.75 (m, 2H), 3.70-3.64 (m, 3-yl]carbamoyl]-6-oxo- 3H), 3.48-3.43(m, 2H), 3.43-3.39 (m, 2H), 3.37- octahydropyrrolo[1,2-a][1,5] 3.29 (m,3H), 2.59-2.53 (m, 2H), 2.45 (s, 3H), diazocin-5-yl]carbamoyl]-1H-2.36-2.26 (m, 1H), 2.23-2.09 (m, 5H), 2.08-1.97indole-5-carbonylphosphonic (m, 3H), 1.95-1.71 (m, 4H), 1.69-1.62 (m,1H), acid 1.59-1.38 (m, 5H), 1.13-1.02 (m, 3H), 0.94 (s, 9H) 157 I-1662-[[(5S,8S,10aR)-8-[[(1S)-3- 1167.45 (400 MHz, DMSO-d₆) δ 12.16-11.95(m, 1H), carbamoyl-1- 11.09 (s, 1H), 8.84-8.69 (m, 2H), 8.46-8.32 (m,(diphenylmethylcarbamoyl) propyl]carbamoyl]- 1H), 8.25-8.13 (m, 1H),7.99-7.89 (m, 2H), 6-oxo-3-[2-[(1r, 4r)-4-[[1-(2,6- 7.54-7.47 (m, 1H),7.44-7.20 (m, 11H), 7.03-6.91 dioxopiperidin-3-yl)-3-methyl- (m, 2H),6.87-6.70 (m, 2H), 6.15-6.03 (m, 1H), 2-oxo-1,3-benzodiazol-5-yl]5.37-5.27 (m, 1H), 4.96-4.86 (m, 1H), 4.45-4.38methyl]cyclohexyl]acetyl]- (m, 2H), 3.94-3.70 (m, 5H), 3.52-3.50 (m,1H), octahydropyrrolo[1,2-a][1,5] 3.33-3.31(m, 4H), 2.90 (s, 3H),2.74-2.70 (m, diazocin-5-yl]carbamoyl]-1H- 2H), 2.69-2.58 (m, 1H),2.46-2.31 (m, 2H), 2.30- indole-5-carbonylphosphonic 1.85 (m, 7H),1.81-1.58 (m, 8H), 1.50-1.39 (m, acid 1H), 1.06-0.90 (m, 4H) 158 I-1692-[[(5S,8S,10aR)-8-[[(1S)-3- 1183.15 (400 MHz, DMSO-d₆) δ 11.88-11.82(m, 1H), carbamoyl-1-(diphenylmethylcarbamoyl) 1118-11.06 (m, 1H),9.49-9.38 (m, 1H), 8.63- propyl]carbamoyl]- 8.51 (m, 1H), 8.22 (d, J =8.0 Hz, 1H), 7.81 (d, J = 3-(4-[4-[1-(2,6-dioxopiperidin- 8.9 Hz, 1H),7.49-7.18 (m, 14H), 7.01-6.92 (m, 3-yl)-3-methyl-2-oxo-1,3- 4H), 6.11(d, J = 8.4 Hz, 1H), 5.28 (dd, J = 12.6,benzodiazol-5-yl]piperidin-1-yl] 5.2 Hz, 1H), 5.14-5.06 (m, 1H),4.50-4.20 (m, butanoyl)-6-oxo-octahydropyrrolo 4H), 4.20-3.58 (m, 2H),3.35 (s, 3H), 3.24-2.75 [1,2-a][1,5]diazocin-5- (m, 10H), 2.75-2.57 (m,3H), 2.46-2.25 (m, 4H), yl]carbamoyl]-1H-indole-5- 2.23-1.82 (m, 10H),1.74 (m, 4H), 1.41 (m, 1H) carbonylphosphonic acid 159 I-170 diammonium2-[[(2S,11S)-2- 1214.55 (400 MHz, DMSO-d₆) δ 11.92-11.84 (m, 1H),[[(2S)-4-carbamoyl-1-[3-[4-(2- 8.99-8.93 (m, 3H), 8.68-8.62 (m, 1H),8.02-7.91 [[(2S)-1-[(2S,4R)-4-hydroxy- (m, 3H), 7.46-7.35 (m, 6H),7.28-7.19 (m, 1H), 2-([[4-(4-methyl-1,3-thiazo1-5- 7.16-7.03 (m, 5H),6.98-6.62 (m, 1H), 6.77-6.71 yl)phenyl]methyl]carbamoyl) (m, 1H),5.12-5.04 (m, 2H), 4.72-4.64 (m, 2H), pyrrolidin-1-yl]-3,3-dimethyl-4.58-4.52 (m, 2H), 4.49-4.39 (m, 4H), 3.82-3.771-oxobutan-2-yl]carbamoyl] (m, 1H), 4.38-4.34 (m, 1H), 4.27-4.17(m, 2H),ethyl)phenyl]propoxy]butan-2- 3.86-3.74 (m, 1H), 3.69-3.64 (m, 5H),2.81-2.72 yl]carbamoyl]-12-oxo-1- (m, 3H), 2.45 (s, 3H), 2.44-2.42 (m,3H), 2.07- azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 2.02(m, 4H), 1.94-1.87 (m, 2H), 1.96-1.85 (m,4(13),5,7-trien-11-yl]carbamoyl]- 1H), 1.82-1.76 (m, 4H), 1.61-1.56 (m,1H), 0.89 1H-indole-5- (s, 9H) carbonylphosphonate 160 I-1712-[[(2S,11S)-2-[[(2S)-4-carbamoyl- [(M − (400 MHz, DMSO-d₆) δ 9.05-8.96(m, 2H), 8.73- 1-[(2Z)-8-[[(2S)-1-[(2S, 1)]⁻ = 8.19 (m, 2H), 7.96-7.82(m, 3H), 7.64-7.35 (m, 4R)-4-hydroxy-2-([[4-(4- 1176.70 8H), 7.25-7.00(m, 3H), 6.82-6.62 (m, 1H), 5.56- methyl-1,3-thiazol-5-yl)phenyl] 5.39(m 4H) 4.82-4.12 (m, 8H), 4.05-3.96 (m, methyl]carbamoyl)pyrrolidin-1-2H) 3.82-3.75,, (m 2H) 3.73-3.64 (m, 3H), 3.34-yl]-3,3-dimethyl-1-oxobutan- 3.15, (m , 6H), 2.45, (s, 3, H), 2.30-1.80(m, 12H), 2-yl]carbamoyl]oct-2-en-1-yl] 1.58-1.21 (m, 4H), 0.95 (s, 9H)oxy]butan-2-yl]carbamoyl]-12- oxo-1-azatricyclo[6.4.1.0{circumflex over( )} [4,13]]trideca-4(13),5,7-trien- 11-yl]carbamoyl]-1H-indole-5-carbonylphosphonic acid 161 I-172 2-[[(5S,8S,10aR)-3-acetyl-8- 1202.50(400 MHz, DMSO-d₆) δ 9.04-8.92 (m, 2H), 8.59-[[(1S)-3-carbamoyl-1-[(7-[[(2S)- 8.53 (m, 1H), 8.20-8.12 (m, 2H),7.91-7.15 (m, 1-[(2S,4R)-4-hydroxy-2-([[4- 10H), 7.01-6.43 (m, 2H),5.10-5.06 (m, 2H), (4-methyl-1,3-thiazol-5-yl) 4.57-4.53 (m, 1H),4.41-4.37 (m, 4H), 4.28-4.19 phenyl]methyl]carbamoyl) (m, 3H), 3.91-3.53(m, 6H), 3.05-3.01 (m, 4H), pyrrolidin-1-yl]-3,3-dimethyl-1- 2.44 (s,3H), 2.32-2.01 (m, 9H), 1.96-1.67 (m, oxobutan-2-yl]carbamoyl] 6H),1.54-1.12 (m, 12H), 0.93 (s, 9H) heptyl)carbamoyl]propyl]carbamoyl]-6-oxo-octahydropyrrolo [1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5- carbonylphosphonic acid 162 I-1732-[[(5S,8S,10aR)-3-acetyl-8- 1216.65 (400 MHz, DMSO-d₆) δ 12.12-11.98(m, 1H), [(1S)-3-carbamoyl-1-[(8-[[(2S)- 9.05-8.95 (m, 2H), 8.63-8.44(m, 1H), 8.18-8.09 1-[(2S,4R)-4-hydroxy-2-([[4- (m, 1H), 7.97 (d, J =8.8 Hz, 1H), 7.89-7.79 (m, (4-methyl-1,3-thiazol-5-yl) 2H), 7.48-7.39(m, 6H), 7.31-7.24 (m, 2H), 6.82- phenyl]methyl]carbamoyl) 6.76 (m, 1H),5.08-4.92 (m, 2H), 4.62-4.58 (m, pyrrolidin-1-yl]-3,3-dimethyl-1- 1H),4.51-4.38 (m, 3H), 4.37-4.31 (m, 1H), 4.29-oxobutan-2-yl]carbamoyl]octyl) 4.14 (m, 3H), 3.92-3.61 (m, 6H),3.11-2.98 (m, carbamoyl]propyl]carbamoyl]- 3H), 2.45 (s, 3H), 2.32-2.18(m, 4H), 2.13-2.00 6-oxo-octahydropyrrolo[1,2- (m, 6H), 1.96-1.60 (m,7H), 1.57-1.33 (m, 5H), a][1,5]diazocin-5-yl]carbamoyl]- 1.25-1.21 (m,8H), 0.94 (s, 9H) 1H-indole-5-carbonylphosphonic acid 163 I-1742-[[(5S,8S,10aR)-8-[[(1S)-3- 1355.25 (300 MHz, DMSO-d₆) δ 12.18-12.01(m, 1H), carbamoyl-1- 8.99 (s, 1H), 8.8.-8.76 (m, 2H), 8.58-8.56 (m,(diphenylmethylcarbamoyl) 1H), 8.42 (d, J = 6.7 Hz, 1H), 8.27-8.13 (m,1H), propyl]carbamoyl]- 7.97 (d, J = 8.8 Hz, 1H), 7.84-7.81 (m, 1H),7.53 6-oxo-3-[2-[(1s,4s)-4-[[1-(2,6- (d, J = 8.7 Hz, 1H), 7.44-7.35 (m,8H), 7.31-7.27 dioxopiperidin-3-yl)-3-methyl- (m, 8H), 6.80-6.70 (m,1H), 6.11 (dd, J = 8.5, 4.7 2-oxo-1,3-benzodiazol-5-yl] Hz 1H),5.00-4.95 (m, 2H), 4.59-4.52 (m, 1H), methyl]cyclohexyl]acetyl]-4.4,8-4.34 (m, 5H), 4.28-4.18 (m, 2H), 3.97-3.90octahydropyrrolo[1,2-a][1,5] (m, 1H), 3.81-3.76 (m, 1H), 3.69-3.64 (m,4H), diazocin-5-yl]carbamoyl]-1H- 3.32-3.27 (m, 4H), 2.94-2.57 (m, 1H),2.45 (s, indole-5-carbonylphosphonic 3H), 2.33-2.21 (m, 1H), 2.15-2.11(m, 5H), 2.06- acid 1.99 (m, 2H), 1.94-1.87 (m, 2H), 1.85-1.61 (m, 1H),1.56-1.52 (m, 1H), 1.32-1.27 (m, 11H), 0.94 (s, 9H) 164 I-176 diammonium2-[[(2S,11S)-2- 1240.01 (400 MHz, DMSO-d₆) δ 11.91 (s, 1H), 9.02-8.84[(3S,4R)-1-carbamoyl-4-([4- (m, 3H), 8.64-8.53 (m, 1H), 8.08-7.84 (m,3H), [3-([[(2S)-1-(2S,4R)-4-hydroxy- 7.45-7.37 (m, 6H), 7.34-7.05 (m,11H), 7.02-6.98 2-([[4-(4-methyl-1,3-thiazol- (m, 1H), 6.70 (s, 1H),5.14-5.10 (m, 1H), 4.68 (t, 5-yl)phenyl]methyl]carbamoyl) J = 7.8 Hz,1H), 4.56 (dd, J = 9.4, 4.0 Hz, 1H), pyrrolidin-1-yl]-3,3-dimethyl-4.47-4.36 (m, 5H), 4.25-4.20 (m, 1H), 3.85-3.771-oxobutan-2-yl]carbamoyl] (m, 2H), 3.70-3.63 (m, 2H), 3.46-3.43 (m,3H), methyl)cyclobutyl]phenyl] 3.21-3.07 (m, 1H), 2.94-2.85 (m, 1H),2.74-2.54 methoxy)pentan-3-yl]carbamoyl]- (m, 1H), 2.46-2.44 (m, 3H),2.42-2.33 (m, 1H), 12-oxo-1-azatricyclo[6.4.1. 2.28-1.99 (m, 7H),1.96-1.67 (m, 4H), 1.60-1.50 0{circumflex over( )}4,13]]trideca-4(13),5,7- (m, 1H), 1.09-1.07 (m, 3H), 0.96-0.94 (m,9H). trien-11-yl]carbamoyl]-1H-indole- 5-carbonylphosphonate 165 I-1772-[[(5S,8S,10aR)-8-[[(1S)-3- 1168.70 (400 MHz, DMSO-d₆) δ 12.06-11.90(m, 1H), carbamoyl-1- 11.08 (s, 1H), 9.15-9.01 (m, 1H), 8.67 (s, 1H),(diphenylmethylcarbamoyl) 8.26-8.15 (m, 1H), 7.98-7.75 (m, 1H),7.61-7.55 propyl]carbamoyl]- (m, 1H), 7.37-7.25 (m, 12H), 7.18-6.81 (m,4H), 3-(3-[4-[1-(2,6-dioxopiperidin- 6.11 (d, J = 8.3 Hz, 1H), 5.38-5.31(m, 1H), 5.22- 3-yl)-3-methyl-2-oxo-1,3- 5.16 (m, 1H), 4.42-4.33 (m,4H), 4.02-3.51 (m, benzodiazol-5-yl]piperidin-1-yl] 6H), 3.30 (s, 3H),3.10-2.82 (m, 7H), 2.75-2.57 propanoyl)-6-oxo-octahydropyrrolo (m, 2H),2.30-1.82 (m, 12H), 1.78-1.54 (m, 6H) [1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5- carbonylphosphonic acid 166 I-178 diammonium2-[[(2S,11S)-2- 1283.50 (400 MHz, DMSO-d₆) δ 12.07-11.85 (m, 1H),[(3S,4R)-1-carbamoyl-4-[(4- 8.99-8.93 (m, 2H), 8.64-8.58 (m, 1H),8.04-7.67 [[1-([[(2S)-1-[(2S,4R)-4-hydroxy- (m, 2H), 7.60-7.42 (m, 6H),7.31-6.52 (m, 10H), 2-([[4-(4-methyl-1,3-thiazol- 5.16-5.10 (m, 2H),4.78-4.65 (m, 1H), 4.56-4.22 5-yl)phenyl]methyl]carbamoyl) (m, 8H),3.86-3.79 (m, 1H), 3.72-3.56 (m, 2H), pyrrolidin-1-yl]-3,3-dimethyl-3.51-3.44 (m, 2H), 3.02-2.97 (m, 1H), 2.92-2.661-oxobutan-2-yl]carbamoyl] (m, 4H), 2.55 (s, 3H), 2.46-2.44 (m, 5H),2.35- methyl)piperidin-4-yl]methyl] 2.14 (m, 1H), 2.16-1.85 (m, 7H),1.81-1.73 (m, phenyl)methoxy]pentan-3-yl] 1H), 1.61-1.45 (m, 5H),1.25-1.19 (m, 2H), 1.10- carbamoyl]-12-oxo-1-azatricyclo 1.06 (m, 3H),0.94 (s, 9H) [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]- 1H-indole-5-carbonylphosphonate 167I-179 2-[[(2S,11S)-2-[[(2S)-4- [(M − (400 MHz, CD₃OD) δ 9.02-8.98 (m,1H), 8.91- carbamoyl-1-([[4-(4-[[(2S)-1-[(2S, 1)]⁻ = 8.86 (m, 1H),8.10-8.04 (m, 1H), 7.53-7.38 (m, 4R)-4-hydroxy-2-([[4-(4-methyl- 1225.455H), 7.35-7.25 (m, 2H), 7.18-7.13 (m, 3H), 7.09-1,3-thiazol-5-yl)phenyl]methyl] 7.03 (m, 2H), 5.22-5.05 (m, 1H),4.74-4.44 (m, carbamoyl)pyrrolidin-1- 6H), 4.41-4.21 (m, 2H), 4.20-4.02(m, 1H), 3.96- yl]-3,3-dimethyl-1-oxobutan-2- 3.77 (m, 2H), 3.65-3.47(m, 2H), 3.28-3.09 (m, yl]carbamoyl]butyl)phenyl] 4H), 2.82-2.53 (m,4H), 2.48 (s, 3H), 2.39-2.19 methyl](methyl)amino)butan- (m, 5H),2.14-2.05 (m, 1H), 1.98-1.68 (m, 2H), 2-yl]carbamoyl]-12-oxo-1-1.62-1.56 (m, 4H), 1.55-1.42 (m, 3H), 1.42-1.27azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] (m, 1H), 1.05 (s, 9H)trideca-4(13),5,7-trien-11-yl] carbamoyl]-1H-indole-5-carbonylphosphonic acid 168 I-180 2-[[(5S,8S, 10aR)-3-acetyl-8- 1230.35(400 MHz, DMSO-d₆) δ 12.03-11.96 (m, 1H),[[(1S)-3-carbamoyl-1-[(9-[[(2S)- 9.01-8.77 (m, 2H), 8.62-8.45 (m, 1H),8.22-7.93 1-(2S,4R)-4-hydroxy-2-([[4- (m, 1H), 7.90-7.82 (m, 3H),7.46-7.33 (m, 6H), (4-methyl-1,3-thiazol-5-yl) 7.33-7.16 (m, 2H),6.85-6.70 (m, 1H), 5.14-5.02 phenyl]methyl]carbamoyl) (m, 2H), 4.57-4.52(m, 1H), 4.46-4.42 (m, 3H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.37-4.33(m, 1H), 4.27-4.18 (m, 3H), 3.91-3.49 oxobutan-2-yl]carbamoyl] (m, 6H),3.06-2.99 (m, 3H), 2.47-2.43 (m, 3H), nonyl)carbamoyl]propyl]carbamoyl]-2.32-2.15 (m, 5H), 2.17-2.00 (m, 5H), 1.96-1.85 6-oxo-octahydropyrrolo(m, 2H), 1.86-1.59 (m, 3H), 1.57-1.32 (m, 6H),[1,2-a][1,5]diazocin-5-yl] 1.25-1.21 (m, 11H), 0.94 (s, 9H)carbamoyl]-1H-indole-5- carbonylphosphonic acid 169 I-1812-[[(5S,8S,10aR)-8-[[(1R)-3- 1141.15 (400 MHz, DMSO-d₆) δ 12.25-11.96(m, 1H), carbamoyl-1- 11.08 (s, 1H), 8.81 (s, 1H), 8.67 (d, J = 9.1 Hz,(diphenylmethylcarbamoyl) 1H), 8.61-8.57 (m, 1H), 8.46-8.42 (m, 1H),7.97- propyl]carbamoyl]- 7.93 (m, 1H), 7.87-7.83 (m, 1H), 7.54-7.44 (m,3-[7-[1-(2,6-dioxopiperidin-3- 3H), 7.43-7.27 (m, 4H), 7.30-7.16 (m,5H), 7.20- yl)-3-methyl-2-oxo-1,3- 7.09 (m, 1H), 7.06-6.98 (m, 3H),6.90-6.81 (m, benzodiazol-5-yl]heptanoyl]-6- 2H), 6.76 (s, 1H),6.25-6.76 (m, 1H), 5.36-5.30 oxo-octahydropyrrolo[1,2-a][1,5] (m, 1H),4.89-4.62 (m, 1H), 4.52-4.14 (m, 3H), diazocin-5-yl]carbamoyl]-1H-3.96-3.91 (m, 1H), 3.85-3.81 (m, 1H), 3.37-3.28indole-5-carbonylphosphonic (m, 6H), 3.15-3.00 (m, 1H), 2.96-2.84 (m,1H), acid 2.73-2.55 (m, 4H), 2.24-2.19 (m, 1H), 2.16-2.03 (m, 3H), 1.97(m, 6H), 1.80-1.45 (m, 4H), 1.37- 1.33 (m, 4H) 170 I-1822-[[(2S,11S)-2-[[(1S)-3-carbamoyl- [(M − (400 MHz, DMSO-d₆) δ 12.08 (s,1H), 11.08 (s, 1-(diphenylmethylcarbamoyl) 1)]⁻ = 1H), 8.94-8.90 (m,1H), 8.87-8.70 (m, 2H), 8.23- propyl]carbamoyl]-6-[7- 114.45 8.19 (m,1H), 7.95 (d, J = 8.7 Hz, 1H), 7.57-7.39 [1-(2,6-dioxopiperidin-3-yl)-(m, 2H), 7.39-7.16 (m, 11H), 7.06-6.95 (m, 2H),3-methyl-2-oxo-1,3-benzodiazol- 6.95-6.87 (m, 3H), 6.77-6.75 (m, 1H),6.10-6.06 5-yl]heptyl]-12-oxo-1- (m, 1H), 5.35-5.30 (m, 1H), 5.14-5.10(m, 1H), azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-4.66-4.64 (m, 1H), 4.35-4.31 (m, 1H), 3.50-3.414(13),5,7-trien-11-yl]carbamoyl]- (m, 2H), 3.41-3.32 (m, 3H), 3.31-3.02(m, 3H), 1H-indole-5-carbonylphosphonic 2.95-2.86 (m, 3H), 2.77-2.65 (m,2H), 2.64-2.56 acid (m, 3H), 2.22-2.18 (m, 2H), 2.06-2.02 (m, 3H),1.95-1.70 (m, 2H), 1.66-1.49 (m, 4H), 1.35-1.30 (m, 6H) 171 I-1832-[[(5S,8S,10aR)-8-[[(3S,4R)- 1144.55, (400 MHz, DMSO-d₆) δ 12.15-11.92(m, 1H), 4-[(4-bromophenyl)methoxy]- 1146.55 11.08 (s, 1H), 8.89-8.64(m, 2H), 8.40-7.69 (m, 1-carbamoylpentan-3-yl] 2H), 7.59-7.35 (m, 4H),7.32-6.93 (m, 5H), 6.86- carbamoyl]-3-[7-[1-(2,6- 6.82 (m, 1H),6.79-6.55 (m, 1H), 5.35-5.24 (m, dioxopiperidin-3-yl)-3-methyl-2-oxo-1H), 5.04-4.88 (m, 1H), 4.62-4.28 (m, 4H), 4.22-1,3-benzodiazol-5-yl]heptanoyl]- 4.17 (m, 1H), 3.94-3.75 (m, 4H),3.47-3.36 (m, 6-oxo-octahydropyrrolo 3H) 3.33-3.27 (m, 3H) 2.97-2.83 (m,1H), 2.74- [1,2-a][1,5]diazocin-5-yl] 2.62 (m, 2H), 2.61-2.54 (m, 3H),2.49-2.26 (m, carbamoyl]-1H-indole-5- 1H), 2.24-1.86 (m, 5H), 1.85-1.62(m, 4H), 1.60- carbonylphosphonic acid 1.50 (m, 5H), 1.43-1.23 (m, 4H),1.15-0.98 (m, 4H) 172 I-184 2-[[(5S8S,10aR)-8-[[(3S,4R)- 1066.85 (400MHz, DMSO-d₆) δ 12.30-11.92 (m, 1H), 4-(benzyloxy)-1-carbamoylpentan-11.08 (s, 1H), 8.80 (s, 1H), 8.49 (d, J = 6.8 Hz,3-yl]carbamoyl]-3-[7-[1- 1H), 8.01-7.76 (m, 2H), 7.57-7.40 (m, 2H),7.36- (2,6-dioxopiperidin-3-yl)-3- 7.25 (m, 5H), 7.23-7.08 (m, 1H),7.03-6.95 (m, methyl-2-oxo-1,3-benzodiazol- 2H), 6.85 (dd, J = 7.8, 6.1Hz, 1H), 6.79-6.53 (m, 5-yl]heptanoyl]-6-oxo- 1H), 5.35-5.25 (m, 1H),5.03-4.88 (m, 1H), 4.54- octahydropyrrolo[1,2-a][1,5] 4.35 (m, 2H),4.34-4.16 (m, 1H), 3.88 (d, J = 13.5 diazocin-5-yl]carbamoyl]-1H- Hz,1H), 3.84-3.69 (m, 2H), 3.52-3.35 (m, 4H), indole-5- 3.35-3.30 (m, 1H),3.29 (s, 3H), 2.98-2.81 (m, carbonylphosphonic 1H), 2.75-2.54 (m, 5H),2.48-2.27 (m, 1H), 2.24- acid 2.05 (m, 3H), 2.05-1.89 (m, 3H), 1.89-1.71(m, 3H), 1.72-1.64 (m, 1H), 1.62-1.45 (m, 5H), 1.43- 1.28 (m, 4H),1.12-1.00 (m, 4H) 173 I-185 diammonium 2-[[(2S,11S)-2- 1246.70 (400 MHz,CD₃OD) δ 8.97 (s, 1H), 8.86 (s, 1H), [[(2S)-4-carbamoyl-1-[3-(5- 8.09(d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H),[[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.46-7.36 (m, 4H), 7.35 (s, 1H),7.18-7.02 (m, [[(1S)-1-[4-(4-methyl-1,3- 4H), 6.78-6.68 (m, 3H), 5.17(dd, J = 10.8, 3.3 thiazol-5-yl)phenyl]ethyl] Hz, 1H), 5.01-4.97 (m,1H), 4.80-4.75 (m, 3H), carbamoyl]pyrrolidin-1-yl]-3,3- 4.62-4.56 (m,2H), 4.43 (s, 1H), 4.24-4.17 (m, dimethyl-1-oxobutan-2-yl]carbamoyl]1H), 4.02-3.97 (m, 2H), 3.88 (d, J = 11.0 Hz, 1H),pentyl)phenoxy]butan-2-yl] 3.80-3.72 (m, 2H), 3.62-3.45 (m, 2H), 3.35(s, carbamoyl]-12-oxo-1-azatricyclo 1H), 3.28-3.22 (m, 2H), 3.03 (d, J =16.1 Hz, 1H), [6.4.1.0{circumflex over ( )}[4,13]]trideca-4 2.58-2.52(m, 4H), 2.10-1.85 (m, 4H), 1.58-1.56 (13),5,7-trien-11-yl]carbamoyl]-(m, 4H), 1.50-1.45 (m, 3H), 1.31-1.26 (m, 3H),1H-indole-5-carbonylphosphonate 1.03 (s, 9H) 174 I-186 diammonium2-[[(2S,11S)-2- 1246.70 (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 8.99 (s,[[(3S,4R)-1-carbamoyl-4-[[2- 1H), 8.95-8.85 (m, 2H), 8.60-8.53 (m, 1H),7.99- fluoro-4-(4-[[(2S)-1-[(2S,4R)-4- 7.83 (m, 3H), 7.45-7.38 (m, 5H),7.35-7.05 (m, hydroxy-2([[4-(4-methyl-1, 5H), 7.00 (dd, J = 9.2, 6.1 Hz,2H), 6.92 (d, J = 3-thiazol-5-yl)phenyl]methyl] 7.8 Hz, 1H), 6.68 (s,1H), 5.20-5.05 (m, 2H), carbamoyl)pyrrolidin-1-yl]-3, 4.73-4.63 (m, 1H),4.55 (d, J = 9.3 Hz, 1H), 4.53- 3-dimethyl-1-oxobutan-2-yl] 4.30 (m,4H), 4.25-4.20 (m, 1H), 3.78 (s, 1H), carbamoyl]butyl)phenyl] 3.71-3.60(m, 2H), 3.50-3.41 (m, 3H), 3.20-3.04 methoxylpentan-3-yl]carbamoyl]-(m, 3H), 2.94-2.82 (m, 1H), 2.68 (s, 1H), 2.45 (s,12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} 3H), 2.37-1.83 (m,7H), 1.76 (s, 2H), 1.56-1.47 [4,13]]trideca-4(13),5,7-trien- (m, 6H),1.27-1.12 (m, 2H), 1.15-1.05 (m, 3H), 11-yl]carbamoyl]-1H-indole- 0.94(s, 9H) 5-carbonylphosphonate 175 I-187 2-[[(2S,11S)-2-[[(1S)-3- 1227.35(300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.00 (s,carbamoyl-1-([[3-(4-[[(2S)-1-[(2S, 1H), 8.94-8.91 (m, 1H), 8.63-8.58 (m,1H), 8.45- 4R)-4-hydroxy-2-([[4-(4- 8.39 (m, 1H), 8.26 (d, J = 7.7 Hz,1H), 7.98-7.91 methyl-1,3-thiazol-5-yl)phenyl] (m, 2H), 7.47-7.37 (m,5H), 7.30-6.95 (m, 3H), methyl]carbamoyl)pyrrolidin-1-yl]- 7.14-7.10 (m,1H), 7.08-6.96 (m, 6H), 6.80 (s, 3,3-dimethyl-1-oxobutan-2- 1H), 5.17(d, J = 10.5 Hz, 1H), 4.72-4.68 (m, 1H), yl]carbamoyl]butyl)phenyl] 4.57(d, J = 9.0 Hz, 1H), 4.51-4.32 (m, 3H), 4.29- methyl]carbamoyl)propyl]4.21 (m, 4H), 3.67 (s, 3H), 3.53-3.47 (m, 4H),carbamoyl]-12-oxo-1-azatricyclo 3.25-2.94 (m, 4H), 2.46 (s, 3H),2.32-2.23 (m, [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13), 3H),2.19-2.04 (m, 4H), 1.94-1.87 (m, 3H), 1.59- 5,7-trien-11-yl]carbamoyl]-1.45 (m, 4H), 0.95 (s, 9H) 1H-indole-5-carbonylphosphonic acid 176 I-188diammonium 2-[[(2S,11S)-2- 1260.75 ¹H NMR (300 MHz, DMSO-d₆) δ 11.89 (s,1H), [[(3S,4R)-1-carbamoyl-4-[[3- 9.00 (s, 1H), 8.99-8.86 (m, 2H), 8.39(d, J = 7.7 fluoro-4-(4-[[(2S)-1-[(2S,4R)-4- Hz, 1H), 7.97-7.82 (m, 3H),7.49-7.37 (m, 5H), hydroxy-2-[[(1S)-1-[4-(4- 7.21-7.13 (m, 2H),7.12-6.92 (m, 6H), 6.70 (s, methyl-1,3-thiazol-5-yl)phenyl] 1H),5.18-5.10 (m, 2H), 4.95-4.89 (m, 1H), 4.72-ethyl]carbamoyl]pyrrolidin-1-yl]- 4.67 (m 1H), 4.52 (d, J = 9.2 Hz, 1H),4.43 (s, 3,3-dimethyl-1-oxobutan-2- 3H), 4.2,8 (s, 1H), 3.82-3.78 (m,1H), 3.60 (s, yl]carbamoyl]butyl)phenyl] 2H), 3.48-3.44 (m, 2H),3.25-3.05 (m, 2H), 2.88 methoxy]pentan-3-yl]carbamoyl]- (d, J = 16.6 Hz,1H), 2.62-2.53 (m, 2H), 2.46 (s, 12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )}[4,13]] 3H), 2.26-2.22 (m, 3H), 2.19-1.97 (m, 5H), 1.79-trideca-4(13),5,7- 1.75 (m, 3H), 1.52-1.47 (m, 4H), 1.40-1.36 (m,trien-11-yl]carbamoyl]-1H- 3H), 1.26-1.24 (m, 1H), 1.09 (s, 3H), 0.94(s, 9H) indole-5-carbonylphosphonate 177 I-189 diammonium2-[[(2S,11S)-2-[ 1232.55 (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 8.99 (s,[(2S)-4-carbamoyl-1-[2-fluoro- 1H), 8.98-8.94 (m, 1H), 8.91 (s, 1H),8.40 (d, J = 3-(4-[[(2S)-1-[(2S,4R)-4- 7.8 Hz, 1H), 8.16 (d, J = 7.4 Hz,1H), 8.00-7.93 hydroxy-2-[[(1S)-1-[4-(4-methyl- (m, 1H), 7.84 (d, J =9.3 Hz, 1H), 7.47-7.37 (m, 1,3-thiazol-5-yl)phenyl]ethyl] 6H), 7.28 (s,1H), 7.11-7.07 (m, 2H), 7.01-6.97 carbamoyl]pyrrolidin-1-yl]-3, (m, 3H),6.84-6.08 (m, 1H), 6.78-6.74 (m, 1H), 3-dimethyl-1-oxobutan-2-yl] 5.09(dd, J = 10.7, 2.9 Hz, 1H), 4.96-4.89 (m, carbamoyl]butyl)phenoxy] 1H),4.70-4.65 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H),butan-2-yl]carbamoyl]-12-oxo-1- 4.48-4.42 (m, 1H), 4.30-4.26 (m, 1H),4.02-3.92 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] (m, 3H),3.63-3.59 (m, 3H), 3.49-3.43 (m, 2H), trideca-4(13),5,7-trien-11-yl]3.21-3.19 (m, 2H), 3.14-3.09 (m, 2H), 2.89 (d, J =carbamoyl]-1H-indole-5-carbonyl 16.6 Hz, 1H), 2.63-2.57 (m, 3H), 2.46(s, 3H), phosphonate 2.34-2.29 (m, 1H), 2.25-2.21 (m, 1H), 2.20-2.10 (m,2H), 2.05-2.00 (m, 1H), 1.88-1.75 (m, 2H), 1.75-1.67 (m, 1H), 1.56-1.52(m, 4H), 1.38 (d, J = 7.0 Hz, 3H), 0.94 (s, 9H). 178 I-1902-[[(5S,8S,10aR)-8-[[(1S)-3- 1036.60 (400 MHz, DMSO-d₆) δ 12.19 (s, 1H),11.09 (s, carbamoyl-1-(pyridin-2-yl) 1H), 8.89-8.80 (m, 1H), 8.59-8.52(m, 2H), 8.51- propyl]carbamoyl]-6-oxo-3-[2- 8.47 (m, 1H), 7.97 (dd, J =8.8, 1.7 Hz, 1H), 7.80- [(1s,4s)-4-[[1-(2,6-dioxopiperidin- 7.75 (m,1H), 7.56-7.52 (m, 1H), 7.47 (d, J = 3.8 3-yl)-3-methyl-2-oxo-1,3- Hz,1H), 7.35-7.20 (m, 3H), 7.03-6.94 (m, 2H), benzodiazol-5-yl]methyl]6.88-6.74 (m, 2H), 5.35-5.51 (m, 1H), 5.04-5.00cyclohexyl]acetyl]-octahydropyrrolo (m, 1H), 4.89-4.83 (m, 1H), 4.50 (t,J = 8.5 Hz, [1,2-a][1,5]diazocin-5-yl] 1H), 4.21-4.17 (m, 1H), 3.94 (d,J = 14.1 Hz, 1H), carbamoyl]-1H-indole-5- 3.76 (d, J = 14.5 Hz, 1H),3.29 (s, 2H), 2.94-2.86 carbonylphosphonic acid (m, 1H), 2.70-2.64(m,1H), 2.62-2.58 (m, 5H), 2.21-2.17 (m, 1H), 2.12-2.08 (m, 2H), 2.06-1.98(m, 10H), 1.76-1.72 (m, 3H), 1.48-1.42 (m, 8H), 1.37-1.32 (m, 2H). 179I-191 diammonium 2-[[(2S,11S)-2- 1263.85 (300 MHz, DMSO-d₆) δ 11.92 (s,1H), 9.04- [(2S)-4-carbamoyl-1-[2-chloro- 8.88 (m, 3H), 8.40 (d, J = 7.8Hz, 1H), 8.14 (d, J = 3-(5-[[(2S)-1-[(2S,4R)-4- 7.3 Hz, 1H), 7.97 (d, J= 9.1 Hz, 1H), 7.82 (d, hydroxy-2-[[(1S)-1-[4-(4-methyl- J = 9.2 Hz,1H), 7.46-7.38 (m, 6H), 7.28 (s, 2H), 1,3-thiazol-5-yl)phenyl]ethyl]7.21-7.16 (m, 1H), 7.12-7.07 (m, 2H), 7.02-7.97carbamoyl]pyrrolidin-1-yl]-3, (m, 2H), 6.91 (d, J = 7.6 Hz, 1H) 6.77 (s,1H), 3-dimethyl-1-oxobutan-2-yl] 5.10 (dd, J = 10.8, 2.8 Hz, 1H),4.96-4.91 (m, carbamoyl]pentyl)phenoxy] 1H), 4.72-4.66 (m, 1H), 4.54 (d,J = 9.1 Hz, 1H), butan-2-yl]carbamoyl]-12-oxo- 4.47-4.42 (m, 1H), 4.30(s, 1H), 4.05-3.96 (m, 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]3H), 3.66-3.56 (m, 2H), 3.55-3.43 (m, 1H), 3.23-trideca-4(13),5,7-trien-11-yl] 3.10 (m, 1H), 2.98 (d, J = 16.7 Hz, 1H),2.71-2.65 carbamoyl]-1H-indole-5- (m, 2H), 2.56-2.43 (m, 6H), 2.31-2.23(m, 3H), carbonylphosphonate 2.23-1.97 (m, 3H), 1.85-1.74 (m, 4H),1.58-1.48 (m, 4H), 1.39 (d, J = 7.0 Hz, 3H), 1.35-1.23(m, 2H) 0.95 (s,9H). 180 I-192 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1168.80 (400 MHz, DMSO-d₆) δ12.13 (s, 1H), 11.09 (s, carbamoyl-1- 1H), 8.82-8.76 (m, 2H), 8.70-8.60(m, 1H), 8.25 (diphenylmethylcarbamoyl) (d, J = 8.1 Hz, 1H), 7.96 (d, J= 8.7 Hz, 1H), 7.52 propyl]carbamoyl]- (d, J = 8.7 Hz, 1H), 7.43-7.39(m, 1H), 7.38-7.20 3-(4-[2-[1-(2,6-dioxopiperidin- (m, 12H), 7.06-7.01(m, 2H), 6.89 (d, J = 8.1 Hz, 3-yl)-3-methyl-2-oxo-1,3- 1H), 6.76 (d, J= 26.1 Hz, 1H), 6.11 (d, J = 8.4 benzodiazol-5-yl]ethyl]piperidine- Hz,1H), 5.38-5.30 (m, 1H), 5.00-4.96 (m, 1H), 1-carbonyl)-6-oxo- 4.47-4.43(m, 1H), 4.40-4.32 (m, 1H), 4.18 (s,octahydropyrrolo[1,2-a][1,5]diazocin- 1H), 3.90-3.80 (m, 1H), 3.76 (s,1H), 3.33-3.30 5-yl]carbamoyl]-1H-indole-5- (m, 7H), 3.05-3.02 (m, 1H),2.89-2.86 (m, 1H), carbonylphosphonic acid 2.72-2.60 (m, 3H), 2.24-1.95(m, 6H), 1.90- 1.1.64 (m, 8H), 1.60-1.14 (m, 7H) 181 I-1932-[[(2S,11S)-2-[[(1S)-3-carbamoyl- 1134.65 (300 MHz, DMSO-d₆) δ 12.03(s, 1H), 8.93-8.87 1-(diphenylmethylcarbamoyl) (m, 1H), 8.80-8.77 (m,1H), 8.43-8.38 (m, 1H), propyl]carbamoyl]-7- 8.26-8.24 (m, 1H), 7.97 (d,J = 8.7 Hz, 1H), 7.47- ([5-[1-(2,6-dioxopiperidin-3-yl)- 7.43 (m, 1H),7.41-7.21 (m, 14H), 7.06-6.96 (m, 3-methyl-2-oxo-1,3-benzodiazol- 2H),6.88-6.77 (m, 2H), 6.13-6.10 (m, 1H), 5.47- 5-yl]pentyl]oxy)-12-oxo-5.37 (m, 1H), 4.99-4.95 (m, 1H), 4.49-4.34 (m,1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 2H), 4.21 (s, 1H),3.98-3.90 (m, 1H), 3.72-3.85 trideca-4(13),5,7-trien-11-yl] (m, 1H),3.04 (s, 3H), 2.85-2.70 (m, 1H), 2.64- carbamoyl]-1H-indole-5- 2.58 (m,1H), 2.17-1.22 (m, 2H), 2.05-1.90 (m, carbonylphosphonic acid 6H),1.81-1.77 (m, 3H), 1.63-1.56 (m, 6H), 1.39- 1.31 (m, 5H). 182 I-194diammonium 2-[[(2S,11S)-2- 1200.85 (400 MHz, DMSO-d₆) δ 11.95-11.88 (m,1H), [[(2S)-4-carbamoyl-1-[3-(3- 9.01-8.94 (m, 2H), 8.96-8.89 (m, 1H),8.41 (d, J = [[(2S)-1-[(2S,4R)-4-hydroxy-2-[ 7.8 Hz, 1H), 8.12 (d, J =8.1 Hz, 1H), 8.02-7.95 [(1S)-1-[4-(4-methyl-1,3- (m, 1H), 7.87 (d, J =9.2 Hz, 1H), 7.47-7.38 (m, thiazol-5-yl)phenyl]ethyl] 4H), 7.38 (d, J =8.4 Hz, 2H), 7.31-7.26 (m, 1H), carbamoyl]pyrrolidin-1-yl]-3,3-7.22-7.16 (m, 1H), 7.10 (d, J = 7.6 Hz, 2H), 7.04-dimethyl-1-oxobutan-2-yl] 6.98 (m, 1H) 6.79-6.71 (m, 4H), 5.10 (dd, J =carbamoyl]propyl)phenoxy]butan- 10.7, 2.9 Hz, 1H), 4.94-4.90 (m, 1H),4.70-3.66 2-yl]carbamoyl]-12-oxo-1-azatricyclo (m, 1H), 4.55 (d, J = 9.3Hz, 1H), 4.46-4.38 (m, [6.4.1.0{circumflex over ( )}[4,13]]trideca-41H), 4.29 (t, J = 3.7 Hz, 1H), 4.05-3.85 (m, 4H),(13),5,7-trien-11-yl]carbamoyl]- 3.69-3.57 (m, 3H), 3.51-3.40 (m, 2H),3.27-3.07 1H-indole-5-carbonylphosphonate (m, 3H), 2.89 (d, J = 16.6 Hz,1H), 2.65-2.61 (m,1H), 2.46 (s, 3H), 2.34-2.08 (m, 6H), 2.08- 1.98 (m,1H), 1.90-1.67 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H), 0.95 (s, 9H) 183 I-1952-[[(5S,8S,10aR)-8-[[(1S)-3- 1169.85 (300 MHz, DMSO-d₆) δ 12.16-12.08(m, 1H), carbamoyl-1-[[(4- 11.12-11.04 (m, 1H), 8.85-8.78 (m, 1H), 8.60-methanesulfonylphenyl) 8.51 (m, 2H), 8.31-8.25 (m, 1H), 8.02-7.93 (m,methyl]carbamoyl] 3H), 7.69-7.44 (m, 4H), 7.34-7.21 (m, 1H), 7.05-propyl]carbamoyl]-6-oxo-3- 6.90 (m, 2H), 6.89-6.56 (m, 2H), 5.34 (dd, J= [2-[(1S,4S)-4-[[1-(2,6-dioxopi 12.6, 5.2 Hz, 1H), 5.02-4.89 (m, 1H),4.64-4.35 peridin-3-yl)-3-methyl-2-oxo- (m, 6H), 4.35-4.14 (m, 4H),4.14-3.73 (m, 2H), 1,3-benzodiazol-5-yl]methyl] 3.36 (s, 3H), 3.20 (s,3H), 3.01-2.84 (m, 1H), cyclohexyl]acetyl]- 2.76-2.63 (m, 6H), 2.31-1.62(m, 12H), 1.57-1.30 octahydropyrrolo[1,2-a][1,5] (m, 8H)diazocin-5-yl]carbamoyl]-1H- indole-5-carbonylphosphonic acid 184 I-1962-[[(5S,8S,10aR)-8-[[(1S)-3- 1133.55 (400 MHz, DMSO-d₆) δ 12.12-11.95(m, 1H), carbamoyl-1-[[(4-isopropylphenyl) 11.14-11.06 (m, 1H),8.86-8.81 (m, 1H), 8.59- methyl]carbamoyl]propyl] 8.13 (m, 3H),8.03-7.93 (m, 1H), 7.61-7.42 (m, carbamoyl]-6-oxo-3-[2-[(1S, 2H),7.31-7.22 (m, 1H), 7.21-7.10 (m, 4H), 7.07-4S)-4-[[1-(2,6-dioxopiperidin- 6.93 (m, 2H), 6.90-6.69 (m, 2H), 5.34(dd, J = 3-yl)-3-methyl-2-oxo-1,3- 12.6, 5.5 Hz, 1H), 5.02-4.91 (m, 1H),4.58-4.41 benzodiazol-5-yl]methyl] (m, 2H), 4.36-4.22 (m, 4H), 4.10-3.44(m, 4H), cyclohexyl]acetyl]-octahydropyrrolo 3.33 (s, 3H), 3.01-2.78 (m,2H), 2.76-2.55 (m, [1,2-a][1,5]diazocin-5-yl] 6H), 2.20-2.08 (m, 4H),2.06-1.85 (m, 6H), 1.87- carbamoyl]-1H-indole-5- 1.60 (m, 4H), 1.60-1.30(m, 8H), 1.18 (dd, J = carbonylphosphonic acid 7.0, 2.0 Hz, 6H) 185I-197 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1141.75 (400 MHz, DMSO-d₆) δ12.23-12.08 (m, 1H), carbamoyl-1-[(naphthalen-1-yl 11.08 (d, J = 3.1 Hz,1H), 8.81 (d, J = 3.9 Hz, methyl)carbamoyl]propyl] 1H), 8.53-8.45 (m,2H), 8.33-8.18 (m, 1H), 8.12- carbamoyl]-6-oxo-3-[2-[(1S,4S)- 7.80 (m,4H), 7.58-7.48 (m, 3H), 7.46-7.39 (m, 4-[[1-(2,6-dioxopiperidin-3-yl)-3H), 7.29-7.20 (m 1H), 7.05-6.93 (m, 2H), 6.90-3-methyl-2-oxo-1,3-benzodiazol- (m, 2H), 5.33 (dd, J = 12.7, 5.7 Hz,1H), 5-yl]methyl]cyclohexyl] 5.01-4.85 (m, 1H), 4.82-4.74 (m, 2H),4.63-4.56 acetyl]-octahydropyrrolo[1,2- (m, 1H), 4.52-4.46 (m, 1H),4.32-4.27 (m, 1H), a][1,5]diazocin-5-yl]carbamoyl]- 4.21-4.07 (m, 1H),3.99-3.91 (m, 2H), 3.77- 1H-indole-5-carbonylphosphonic 3.70(m, 1H),3.31 (s, 3H), 2.93-2.86 (m, 1H), acid 2.79-2.55 (m, 6H), 2.20-2.09 (m,3H), 2.07-1.92 (m, 4H), 1.89-1.57 (m, 5H), 1.55-1.46 (m, 2H), 1.50-1.28(m, 9H) 186 I-198 2-[[(2S,11S)-2-[[(1S)-3-carbamoyl- 1118.55 (400 MHz,DMSO-d₆) δ 12.13-11.08 (m, 1H), 1-(diphenylmethylcarbamoyl) 11.12-11.06(m, 1H), 8.94 (d, J = 7.9 Hz, 1H), propyl]carbamoyl]-6-[5- 8.87-8.74 (m,2H), 8.21 (d, J = 7.9 Hz, 1H), 7.95 [1-(2,6-dioxopiperidin-3-yl)- (d, J= 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.52-3-methyl-2-oxo-1,3-benzodiazol- 7.45 (m, 1H), 7.37-7.16 (m, 11H),7.08-6.96 (m, 5-yl]pentyl]-12-oxo-1- 2H), 6.94-6.85 (m, 3H), 6.83-6.76(m, 1H), 6.07 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-(d, J = 8.3 Hz, 1H) 5.34 (dd, J = 12.7, 5.4 Hz,4(13),5,7-trien-11-yl]carbamoyl]- 1H), 5.15-5.10,(m, 1,H), 4.69-4.58 (m,1H), 4.42- 1H-indole-5-carbonylphosphonic 4.36 (m, 1H), 3.33 (s, 3H),3.19-3.04 (m, 2H), acid 2.95-2.86 (m, 2H), 2.77-2.57 (m, 5H), 2.25-2.18(m, 2H), 2.13-1.97 (m, 3H), 1.94-1.87 (m, 2H), 1.84-1.69 (m, 2H),1.68-1.56 (m, 6H), 1.40-1.34 (m, 2H) 187 I-199 diammonium2-[[(2S,11S)-2- 1262.90 (400 MHz, DMSO-d₆) δ 11.95-11.90 (m, 1H),[[(2S)-4-carbamoyl-1-[4-chloro- 9.02-8.95 (m, 2H), 8.94-8.86 (m, 1H),8.41 (d, J = 3-(5-[[(2S)-1-[(2S,4R)-4- 7.7 Hz, 1H), 8.12 (d, J = 8.1 Hz,1H), 7.99- hydroxy-2-[[(1S)-1-[4-(4-methyl- 7.92 (m, 1H), 7.88-7.82 (m,1H), 7.47-7.31 (m, 1,3-thiazol-5-yl)phenyl]ethyl] 6H), 7.31-7.24 (m,2H), 7.09-7.07 (m, 2H), 7.03- carbamoyl]pyrrolidin-1-yl]-3, 6.97 (m,1H), 6.93-6.86(m, 1H), 6.83-6.74 (m, 3-dimethyl-1-oxobutan-2-yl] 2H),5.13-5.05 (m, 1H) 4.97-4.89 (m, 1H), 4.71- carbamoyl]pentyl)phenoxy]4.65,(m, 1H), 4.32,-4.25, (m, 1H), 4.02-3.84 (m,butan-2-yl]carbamoyl]-12-oxo- 3H), 3.62-3.58 (m, 3H), 3.51-3.39 (m, 3H),3.24- 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 3.07 (m, 3H),2.88-2.84 (m, 1H), 2.62-2.58 (m, trideca-4(13),5,7-trien-11-yl] 2H),2.45 (s, 3H), 2.27-2.21 (m, 3H), 2.18-2.08 carbamoyl]-1H-indole-5- (m,4H), 2.07-1.97 (m, 1H), 1.85-1.75 (m, 2H), carbonylphosphonate 1.74-1.66(m, 1H), 1.57-1.44 (m, 4H), 1.38 (d, J = 7.0 Hz, 3H), 1.34-1.22 (m, 2H),0.94 (s, 9H) 188 I-200 2-[[(2S,11S)-2-[[(2S)-4- 1262.80 (400 MHz,DMSO-d₆) δ 11.95-11.86 (m, 1H), carbamoyl-1-[2-chloro-5-(5-[[(2S)-9.01-8.89 (m, 3H), 8.41 (d, J = 7.7 Hz, 1H), 8.131-[(2S,4R)-4-hydroxy-2-[[(1S)- (d, J = 7.5 Hz, 1H), 7.96 (d, J = 8.5 Hz,1H), 7.80 1-[4-(4-methyl-1,3-thiazol-5- (d, J = 9.2 Hz, 1H), 7.48-7.35(m, 6H), 7.34-7.27 yl)phenyl]ethyl]carbamoylipyrrolidin- (m, 2H),7.10-7.06 (m, 2H), 7.06-6.95 (m, 2H), 1-yl]-3,3-dimethyl-1- 6.85-6.78(m, 2H), 5.09-5.07 (m, 1H), 4.92-4.90 oxobutan-2-yl]carbamoyl] (m, 1H),4.68-4.66 (m, 1H), 4.52-4.50 (m, 1H), pentyl)phenoxy]butan-2-yl]4.45-4.43 (m, 1H), 4.29-4.27 (m, 1H), 4.08-4.01carbamoyl]-12-oxo-1-azatricyclo (m, 2H), 4.02-3.93 (s, 1H), 3.66-3.54(m, 3H), [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5, 3.52-3.41(m, 4H), 3.16-3.14 (m, 3H), 2.98-2.96 7-trien-11-yl]carbamoyl]-1H- (m,1H), 2.45 (s, 3H), 2.32-1.98 (m, 7H), 1.89- indole-5-carbonylphosphonic1.70 (m, 3H), 1.51-1.49 (m, 4H), 1.38 (d, J = 7.0 acid Hz, 3H),1.26-1.24 (m, 2H), 0.93 (s, 9H) 189 I-201 2-[[(2S,11S)-2-[[(3R)-1-1227.65 ¹H NMR (400 MHz, DMSO-d₆) δ 12.14-12.05carbamoyl-5-[3-(5-[[(2S)-1-[(2S, (m, 1H), 9.05-8.92 (m, 2H), 8.82-8.73(m, 2H), 4R)-4-hydroxy-2-[[(1S)-1-[4-(4- 8.37 (d, J = 7.8 Hz, 1H),8.01-7.73 (m, 3H), 7.59- methyl-1,3-thiazol-5-yl)phenyl] 7.32 (m, 7H),7.30-7.06 (m, 4H), 7.06-6.91 (m, ethyl]carbamoyl]pyrrolidin- 6H),6.72-6.70 (m, 1H), 5.10-5.07 (m, 1H), 4.96-1-yl]-3,3-dimethyl-1-oxobutan- 4.88 (m, 1H), 4.74-4.64 (m, 1H),4.54-4.50 (m, 2-yl]carbamoyl]pentyl) 1H), 4.43 (t, J = 8.0 Hz, 1H),4.30-4.27 (m, 1H), phenyl]pentan-3-yl]carbamoyl]- 3.71-3.44 (m, 4H),3.26-3.05 (m, 2H), 3.05-2.89 12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )} (m, 1H), 2.48-2.43 (m, 5H), 2.38-2.16 (m, 4H),[4,13]]trideca-4(13),5,7-trien- 2.16-1.95 (m, 4H), 1.86-1.75 (m, 1H),1.72-1.59 11-yl]carbamoyl]-1H-indole- (m, 3H), 1.55-1.47 (m, 5H),1.39-1.36 (m, 3H), 5-carbonylphosphonic acid 1.29-1.18 (m, 2H),0.94-0.93 (m, 9H) 190 I-202 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1167.65 (400MHz, DMSO-d₆) δ 12.11-11.98 (m, 1H), carbamoyl-1- 11.09 (s, 1H),8.81-8.78 (m, 2H), 8.45-8.41 (m, (diphenylmethylcarbamoyl) 1H),8.25-8.21 (m, 1H), 7.96 (d, J = 8.7 Hz, 1H), propyl]carbamoyl]- 7.52 (d,J = 8.7 Hz, 1H), 7.42-7.24 (m, 13H), 6-oxo-34(1s,4s)-4-[2-[1-(2,6-7.03-6.99 (m, 2H), 6.88-6.72 (m, 2H), 6.11 (d, J =dioxopiperidin-3-yl)-3-methyl-2- 8.4 Hz, 1H), 5.38-5.30 (m, 1H),5.01-4.79 (m, oxo-1,3-benzodiazol-5-yl] 1H), 4.46-4.35 (m, 2H),4.29-4.10 (m, 2H), 4.02- ethyl]cyclohexanecarbonyl]- 3.91 (m, 1H),3.79-3.69 (m, 1H), 2.94-2.83 (m, octahydropyrrolo[1,2-a][1,5] 2H),2.74-2.60 (m, 4H), 2.57-2.54 (m, 2H), 2.24- diazocin-5-yl]carbamoyl]-1H-1.98 (m, 6H), 1.94-1.62 (m, 12H), 1.55-1.02 (m,indole-5-carbonylphosphonic 7H) acid 191 I-2032-[[(5S,8S,10aR)-8-[[(1S)-3- 1167.60 (400 MHz, DMSO-d₆) δ 12.12-11.98(m, 1H), carbamoyl-1- 11.09 (s, 1H), 8.81-8.75 (m, 2H), 8.42-8.39 (m,(diphenylmethylcarbamoyl) 1H), 8.26-8.22 (m, 1H), 7.97 (d, J = 8.7 Hz,1H), propyl]carbamoyl]- 7.53 (d, J = 8.3 Hz, 1H), 7.46-7.19 (m, 12H),6-oxo-3-[(1r,4r)-4-[2-[1-(2,6- 7.06-6.97 (m, 2H), 6.89-6.87 (m, 1H),6.78-6.72 dioxopiperidin-3-yl)-3-methyl- (m, 1H), 6.11 (d, J = 8.4 Hz,1H), 5.37-5.32 (m, 2-oxo-1,3-benzodiazol-5-yl] 1H), 5.01-4.79 (m, 1H),4.47-4.33 (m, 2H), 4.24- ethyl]cyclohexanecarbonyl]- 4.11 (m, 1H),4.01-3.90 (m, 1H), 3.81-3.72 (m, octahydropyrrolo[1,2-a][1,5] 1H),3.61-3.40 (m, 4H), 3.26-3.14 (m, 2H), 3.06- diazocin-5-yl]carbamoyl]-1H-3.00 (m, 1H), 2.95-2.85 (m, 1H), 2.75-2.59 (m,indole-5-carbonylphosphonic 5H), 2.23-1.88 (m, 7H), 1.82-1.63 (m, 15H)acid 192 I-204 2-[[(2S,11S)-2-[[(2S)-4- 1262.55 (300 MHz, DMSO-d₆) δ12.05 (s, 1H), 9.06-8.77 carbamoyl-1-[3-chloro-5-(5-[[(2S)- (m, 3H),8.38 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.71-[(2S,4R)-4-hydroxy-2-[[(1S)- Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.80(d, J = 9.2 1-[4-(4-methyl-1,3-thiazol-5- Hz, 1H), 7.58-7.33 (m, 6H),7.25 (s, 1H), 7.13- yl)phenyl]ethyl]carbamoyl] 7.09 (m, 2H), 7.03-6.98(m, 1H), 6.91-6.79 (m, prrolidin-1-yl]-3,3-dimethyl-1- . 2H), 6.76-6.73(m, 2H), 5.12-5.07 (m, 1H), 4.98- oxobutan-2-yl]carbamoyl] 4.90 (m, 1H),4.73-4.67 (m, 1H), 4.53 (d, J = 9.3 pentyl)phenoxy]butan-2-yl] Hz, 1H),4.44 (t, J = 8.0 Hz, 1H), 4.32-4.27 (m, carbamoyl]-12-oxo-1-azatricyclo1H), 4.03-3.91 (m, 3H), 3.67-3.59 (m, 2H), 3.56- [6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13),5, 3.03 (m, 9H), 2.91-2.85 (m, 1H), 2.47(s, 3H), 7-trien-11-yl]carbamoyl]-1H- 2.37-2.19 (m, 2H), 2.19-1.95 (m,3H), 1.91-1.63 indole-5-carbonylphosphonic (m, 3H), 1.61-1.48 (m, 4H),1.39 (d, J = 7.0 Hz, acid 3H), 1.34-1.16 (m, 3H), 0.94 (s, 9H) 193 I-205diammonium 2-[[(2S,11S)-2- 1242.65 (300 MHz, DMSO-d₆) δ 11.93 (s, 1H),9.04-8.83 [[(2S)-4-carbamoyl-1-[3-[5- (m, 3H), 8.40 (d, J = 7.8 Hz, 1H),8.13 (d, J = 8.2 [[(2S)-1-[(2S,4R)-4-hydroxy-2- Hz, 1H), 7.98 (d, J =8.7 Hz, 1H), 7.83 (d, J = 9.2 [[(1S)-1-[4-[4-methyl-1,3- Hz, 1H),7.53-7.17 (m, 11H), 7.13-6.98 (m, 4H),thiazol-5-yl)phenyl]ethyl]carbamoyl] 6.79-6.73 (m, 3H), 5.14-5.10 (m,1H), 4.96-4.89 pyrrolidin-1-yl]-3,3-dimethyl- (m, 1H), 4.73-4.67 (m,1H), 4.59-4.50 (m, 1H), 1-oxobutan-2-yl]carbamoyl] 4.45 (t, J = 8.0 Hz,1H), 4.32-4.27 (m, 1H), 4.08- pentyl)-2-methylphenoxy] 4.02 (m, 1H),3.95-3.84 (m, 2H), 3.70-3.56 (m, butan-2-yl]carbamoyl]-12- 2H),3.53-3.44 (m, 1H), 3.26-3.11 (m, 3H), 2.92-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 2.86 (m, 1H), 2.48(s, 3H), 2.34-2.23 (m, 3H), trideca-4(13),5,7-trien-11-yl] 2.19-2.13 (m,3H), 2.08 (s, 3H), 2.05-2.01 (m, carbamoyl]-1H-indole-5- 1H), 1.89-1.74(m, 3H), 1.59-1.46 (m, 4H), 1.40 carbonylphosphonate (d, J = 6.7 Hz,3H), 1.34-1.26 (m, 2H), 0.95 (s, 9H) 194 I-206 diammonium2-[[(2S,11S)-2- 1241.00 (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.03-8.86[[(2S)-4-carbamoyl-1-[3-(5- (m, 3H), 8.81 (s, 1H), 8.10 (d, J = 8.2 Hz,1H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 8.01-7.86 (m, 2H), 7.45-7.42 (m,2H), 7.38-7.21 ([1-[4-[4-methyl-1,3-thiazo1-5- (m, 6H), 7.16 (t, J = 7.7Hz, 1H), 7.11-7.07 (m, yl)phenyl]cyclopropyl] 2H), 6.99 (t, J = 7.4 Hz,1H), 6.82-6.67 (m, 4H), carbamoyl)pyrrolidin-1-yl]- 5.11-5.08 (m, 1H),4.71-4.66 (m, 1H), 4.55 (d, J = 3,3-dimethyl-1-oxobutan-2-yl] 9.3 Hz,1H), 4.43-4.35 (m, 2H), 4.05-3.94 (m, carbamoyl]pentyl)phenoxy]butan-1H), 3.93-3.88 (m, 2H), 3.68-3.62 (m, 3H), 3.54-2-yl]carbamoyl]-12-oxo-1- 3.38 (m, 2H), 3.29-3.06 (m, 3H), 2.91-2.86 (m,azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 1H), 2.44 (s,3H), 2.34-2.23 (m, 3H), 2.19-2.07 4(13),5,7-trien-11-yl]carbamoyl]- (m,3H), 2.07-1.96 (m, 1H), 1.91-1.83 (m, 2H), 1H-indole-5- 1.77-1.63 (m,1H), 1.62-1.48 (m, 4H), 1.35-1.05 carbonylphosphonate (m, 7H), 0.94 (s,9H) 195 I-207 diammonium 2-[[(2S,11S)-2- [(M − (400 MHz, DMSO-d₆) δ11.88 (s, 1H), 9.00-8.93 [(2S)-4-carbamoyl-1-[2-fluoro- 1)]⁻ = (m, 3H),8.40 (d, J = 7.8 Hz, 1H), 8.16-8.13 (m, 5-(5-[[(2S)-1-[(2S,4R)-4-1244.40 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 9.3 Hz,hydroxy-2-[[(1S)-1-[4-(4-methyl- 1H), 7.67-7.58 (m, 1H), 7.46-7.34 (m,12H), 7.27 1,3-thiazol-5-yl)phenyl]ethyl] (s, 1H), 7.16-6.93 (m, 5H),6.77-6.74 (m, 2H), carbamoyl]pyrrolidin-1-yl]-3, 5.15-5.04 (m, 1H),4.96-4.89 (m, 1H), 4.70-4.66 3-dimethyl-1-oxobutan-2-yl] (m, 1H), 4.52(d, J = 9.3 Hz, 1H), 4.44 (t, J = 8.1 carbamoyl]pentyl)phenoxy] Hz, 1H),4.31-4.27 (m, 1H), 4.04-3.95 (m, 3H), butan-2-yl]carbamoyl]-12-oxo-3.65-3.58 (m, 2H), 3.50-3.43 (m, 1H), 3.27-3.061-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] (m, 1H), 2.92-2.87 (m,1H), 2.46 (s, 3H), 2.37- trideca-4(13),5,7-trien-11-yl] 1.97 (m, 6H),1.95-1.64 (m, 3H), 1.58-1.47 (m, carbamoyl]-1H-indole-5- 4H), 1.38 (d, J= 7.0 Hz, 3H), 1.29-1.23 (m, 2H), carbonylphosphonate 0.93 (s, 9H) 196I-208 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1167.60 (300 MHz, DMSO-d₆) δ12.13-11.95 (m, 1H), carbamoyl-1- 11.08 (s, 1H), 8.93-8.70 (m, 2H),8.46-8.42 (m, (diphenylmethylcarbamoyl) 1H), 8.30-8.18 (m, 1H), 7.98 (d,J = 8.8 Hz, 1H), propyl]carbamoyl]- 7.57-7.41 (m, 2H), 7.41-7.19 (m,11H), 7.14-6.95 3-(5-[3-[1-(2,6-dioxopiperidin- (m, 2H), 6.92-6.64 (m,2H), 6.14-6.09 (m, 1H), 3-yl)-3-methyl-2-oxo-1,3- 5.39-5.30 (m, 1H),5.02-4.88 (m, 1H), 4.58-4.12 benzodiazol-5-yl]cyclobutyl] (m, 4H),4.12-3.53 (m, 4H), 3.33-3.15 (m, 4H), pentanoyl)-6-oxo-octahydropyrrolo2.97-2.87 (m, 1H), 2.80-2.58 (m, 3H), 2.48-2.38[1,2-a][1,5]diazocin-5-yl] (m, 2H), 2.32-1.88 (m, 10H), 1.84-1.56 (m,8H), carbamoyl]-1H-indole-5- 1.51-1.17 (m, 4H) carbonylphosphonic acid197 I-209 diammonium 2-[[(2S,11S)-2- 1241.60 (300 MHz, DMSO-d₆) δ12.15-11.74 (m, 1H), [(1S)-3-carbamoyl-1-[[3-(5- 9.95 (s, 1H), 9.08-8.86(m, 3H), 8.41-8.37 (m, [[(2S)-1-[(2S,4R)-4-hydroxy-2- 2H), 7.98-7.93 (m,1H), 7.81 (d, J = 9.2 Hz, 1H), [[(1S)-1-[4-[4-methyl-1,3- 7.47-7.34 (m,8H), 7.22-7.10 (m, 4H), 7.03-6.97 thiazol-5-yl)phenyl]ethyl]carbamoyl](m, 1H) 6.90-6.86 (m, 1H), 6.80 (s, 1H), 5.22-pyrrolidin-1-yl]-3,3-dimethyl- 5.18 (m, 1H), 4.96-4.89 (m, 1H),4.73-4.69 (m, 1-oxobutan-2-yl]carbamoyl] 1H), 4.53-4.45 (m, 2H),4.33-4.27 (m, 2H), 3.62 pentyl)phenyl]carbamoyl] (s, 3H), 3.25-3.00 (m,5H), 2.47 (s, 3H), 2.30- propyl]carbamoyl]-12-oxo-1- 2.21 (m, 4H),2.19-2.10 (m, 3H), 2.08-1.76 (m, azatricyclo[6.4.1.0{circumflex over( )}[4,13]] 5H), 1.59-1.48 (m, 4H), 1.39 (d, J = 6.9 Hz, 3H),trideca-4(13),5,7-trien-11-yl] 1.32-1.24 (m, 3H), 0.95 (s, 9H)carbamoyl]-1H-indole-5- carbonylphosphonate 198 I-2102-[[(2S,11S)-2-[[(3S,4R)-1- 1228.80 (400 MHz, DMSO-d₆) δ 12.04 (s, 1H),8.99-8.96 carbamoyl-4-[3-(5-[[(2S)-1-[(2S, (m, 2H), 8.84 (s, 1H),8.59-5.55 (m, 1H), 8.05- 4R)-4-hydroxy-2-([[4-(4- 7.96 (m, 2H), 7.86 (d,J = 9.3 Hz, 1H), 7.54-7.35 methyl-1,3-thiazol-5-yl)phenyl] (m, 6H), 7.21(s, 1H), 7.14-7.05 (m, 3H), 7.01- methyl]carbamoyl)pyrrolidin-1- 6.96(m, 1H), 6.75-6.71 (m, 2H), 6.67-6.64 (m, yl]-3,3-dimethyl-1-oxobutan-2H), 5.13-5.07 (m, 1H), 4.71-4.65 (m,1H), 4.57-2-yl]carbamoyl]pentyl)phenoxy] 4.53 (m, 1H), 4.49-4.30 (m, 4H),4.28-4.10 (m, pentan-3-yl]carbamoyl]-1 1H), 3.87-3.8,1 (m, 1H),3.71-3.63 (m, 2H), 3.52- 2-oxo-1-azatricyclo[6.4.1.0{circumflex over( )} 3.29 (m, 4H), 3.23-3.03 (m, 3H), 2.81-2.77 (m,[4,13]]trideca-4(13),5,7-trien- 1H), 2.44 (s, 3H), 2.37-2.17 (m, 3H),2.17-1.97 11-yl]carbamoyl]-1H-indole- (m, 4H), 1.95-1.84 (m, 2H),1.61-1.38 (m, 6H), 5-carbonylphosphonic acid 1.32-1.21 (m, 2H), 1.17 (d,J = 6.0 Hz, 3H), 0.93 (s, 9H) 199 I-211 diammonium 2-[[(2S,11S)-2- [(M −(400 MHz, DMSO-d₆) δ 12.10-11.83 (m, 1H), [[(2S)-4-carbamoyl-1-[3-(4-1)]⁻ = 9.01-8.90 (m, 3H), 8.43-8.38 (m, 1H), 8.11 (d, J =[[(2S)-1-[(2S,4R)-4-hydroxy-2- 1212.35 8.2 Hz, 1H), 7.99-7.93 (m, 1H),7.83 (d, J = 9.2 [[(1S)-1-[4-(4-methyl-1,3-thiazol- Hz, 1H), 7.47-7.29(m, 6H), 7.27 (s, 1H), 7.19- 5-yl)phenyl]ethyl]carbamoyl] 7.15 (m, 1H),7.12-7.08 (m, 2H), 7.03-6.97 (m, pyrrolidin-1-yl]-3,3-dimethyl- 1H),6.76-6.72 (m, 4H), 5.13-5.08 (m, 1H), 4.95- 1-oxobutan-2-yl]carbamoyl]4.89 (m, 1H), 4.70-4.66 (t, J = 8.5 Hz, 1H), 4.55-butyl)phenoxy]butan-2-yl] 4.51 (m, 1H), 4.47-4.43 (m, 1H), 4.31-4.26 (m,carbamoyl]-12-oxo-1-azatricyclo 1H), 4.01-3.97 (m, 1H), 3.92 ? 3.88 (m,2H), 3.61 [6.4.1.0{circumflex over ( )}[4,13]]trideca-4 (s, 3H),3.52-3.40 (m, 3H), 3.26-3.08 (m, 3H), (13),5,7-trien-11-yl]carbamoyl]-2.91-2.87 (m, 1H), 2.46 (s, 3H), 2.29-2.25 (m,1H-indole-5-carbonylphosphonate 5H), 2.16-2.12 (m, 2H), 2.05-2.01 (m,1H), 1.92- 1.65 (m, 2H), 1.51-1.47 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H),0.94 (s, 9H) 200 I-212 2-[[(2S,11S)-2-[[(2S)-4- 1242.40 (400 MHz,DMSO-d₆) δ 12.05 (s, 1H), 9.00-8.96 carbamoyl-1-[3-(5-[[(2S)-1-[(2S,4R)-(m, 2H), 8.86-8.82 (m, 1H), 8.38 (d, J = 7.8 Hz,4-hydroxy-2-[[(1S)-1-[4-(4- 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.99-7.95 (m,1H), methyl-1,3-thiazol-5-yl)phenyl] 7.83-7.79 (m, 1H), 7.55-7.31 (m,6H), 7.25 (s, ethyl]carbamoyl]pyrrolidin- 1H), 7.10-6.92 (m, 2H),7.00-6.88 (m, 2H), 6.75- 1-yl]-3,3-dimethyl-1-oxobutan- 6.73 (m, 1H),6.70-6.60 (m, 2H), 5.09-4.98 (m, 2-yl]carbamoyl]pentyl)-4- 1H),4.93-4.76 (m, 1H), 4.69-4.49 (m, 1H), 4.53- methylphenoxy]butan-2-yl]4.35 (m, 1H), 4.46-4.42 (m, 1H), 4.37-4.26 (m,carbamoyl]-12-oxo-1-azatricyclo 2H), 3.99-3.79 (m, 2H), 3.87-3.68 (m,3H), 3.62- [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13), 3.60 (m,2H), 3.46-3.26 (m, 1H), 3.29-3.04 (m, 5,7-trien-11-yl]carbamoyl]- 2H),2.88-2.86 (m, 1H), 2.45 (s, 3H), 2.28- 1H-indole-5-carbonylphosphonic2.26( m, 4H), 2.20-2.06 (m, 6H), 2.02-1.99 (m, acid 1H), 1.88-1.75 (m,2H), 1.75-1.63 (m, 1H), 1.63- 1.43 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H),1.36-1.27 (m, 2H), 0.94 (s, 9H) 201 I-213 2-[[(2S,11S)-2-[[(2S)-4- [(M −(300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 8.98-8.92carbamoyl-1-[3-(5-[[(2S)-1-[(2S,4R)- 1)]⁻ = (m, 2H), 8.83 (s, 1H), 8.36(d, J = 7.8 Hz, 1H), 4-hydroxy-2-[[(1S)-1-[4-(4- 1240.35 8.07 (d, J =8.1 Hz, 1H), 8.00-7.91 (m, 1H), 7.78 methyl-1,3-thi azol-5-yl)phenyl](d, J = 9.2 Hz, 1H), 7.55-7.33 (m, 6H), 7.24 (s,ethyl]carbamoyl]pyrrolidin- 7.14-6.93 (m, 3H), 6.73 (s, 1H), 6.60-6.491-yl]-3,3-dimethyl-1-oxobutan- (m, 3H), 5.14-5.03 (m, 2H), 4.93-4.89 (m,1H), 2-yl]carbamoyl]pentyl)-5- 4.71-4.67 (m 1H), 4.56-4.37 (m, 3H),4.33-4.18 methylphenoxy]butan-2-yl] (m, 1H), 4.04-3.79 (m, 5H),3.66-3.53 (m, 2H), carbamoyl]-12-oxo-1-azatricyclo 3.52-3.37 (m, 2H),3.17-3.13 (m, 2H), 2.94-2.82 [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13), (m, 1H), 2.45(s, 3H), 2.25-2.22 (m, 6),2.15-1.94 5,7-trien-11-yl]carbamoyl]- (m, 3H), 1.86-1.66 (m, 2H),1.49-1.47 (m, 6H), 1H-indole-5-carbonylphosphonic 1.37 (d, J = 6.9 Hz,3H), 1.31-1.20 (m, 2H), 0.93 acid (s, 9H) 202 I-2142-[[(2S,11S)-2-[[(2S)-4- 1242.80 (400 MHz, DMSO-d₆) δ 12.25-11.90 (m,1H), carbamoyl-1-[5-(5-[[(2S)-1-[(2S,4R)- 9.03-8.91 (m, 3H), 8.39-8.35(m, 1H), 8.16-8.11 4-hydroxy-2-[[(1S)-1-[4-(4- (m, 2H), 7.78 (d, J = 9.1Hz, 1H), 7.59-7.35 (m, methyl-1,3-thiazol-5-yl)phenyl] 6H), 7.28-7.24(m, 1H), 7.06-7.01 (m, 4H), 6.70- ethyl]carbamoyl]pyrrolidin- 6.66 (m,3H), 5.13-5.08 (m, 2H), 4.95-4.89 (m, 1-yl]-3,3-dimethyl-1-oxobutan-1H), 4.70-4.66 (m, 1H), 4.54-4.50 (m, 1H), 4.45-2-yl]carbamoyl]pentyl)-2- 4.41 (m, 1H), 4.30-4.26 (m, 1H), 4.05-4.01 (m,methylphenoxy]butan-2-yl] 1H), 3.91-3.88 (m, 2H), 3.61-3.59 (m, 2H),2.88- carbamoyl]-12-oxo-1-azatricyclo 2.84 (m, 1H), 2.46-2.42 (m, 4H),2.26-2.00 (m, [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13), 12H),1.84-1.73 (m, 4H), 1.58-1.50 (m, 5H), 1.375,7-trien-11-yl]carbamoyl]-1H- (d, J = 7.0 Hz, 3H), 1.28-1.22 (m, 4H),0.93 (s, indole-5-carbonylphosphonic 9H) acid 203 I-2152-[[(2S,11S)-2-[[(2S)-4- 1247.10 (400 MHz, DMSO-d₆) δ 11.99 (s, 1H),9.01-8.94 carbamoyl-1-[4-fluoro-3-(5-[[(2S)- (m, 2H), 8.86 (s, 1H), 8.38(d, J = 7.8 Hz, 1H), 1-[(2S,4R)-4-hydroxy-2-[[(1S)- 8.10 (d, J = 8.2 Hz,1H), 8.00-7.93 (m, 1H), 7.80 1-[4-(4-methyl-1,3-thiazol-5- (d, J = 9.2Hz, 1H), 7.52-7.38 (m, 6H), 7.25 (s, yl)phenyl]ethyl]carbamoyl] 1H),7.13-6.96 (m, 4H), 6.81 (dd, J = 6.2, 3.1 Hz,pyrrolidin-1-yl]-3,3-dimethyl-1- 1H), 6.78-6.70 (m, 2H), 5.13-5.06 (m,1H), 4.95- oxobutan-2-yl]carbamoyl] 4.88 (m, 1H), 4.72-4.68 (m, 1H),4.52 (d, J = 9.3 pentyl)phenoxy]butan-2-yl] Hz, 1H), 4.45-4.42 (m, 1H),4.28 (s, 1H), 4.01- carbamoyl]-12-oxo-1-azatricyclo 3.94 (m, 1H), 3.88(s, 2H), 3.61 (s, 2H), 3.52-3.23 [6.4.1.0{circumflex over( )}4,13]]trideca-4(13),5, (m, 4H), 3.17-3.07 (m, 4H), 2.87 (d, J = 16.7Hz, 7-trien-11-yl]carbamoyl]-1H- 1H), 2.46 (s, 3H), 2.32-2.20 (m, 3H),2.16-2.07 indole-5-carbonylphosphonic (m, 3H), 2.07-1.97 (m, 1H),1.85-1.77 (m, 2H), acid 1.76-1.66 (m, 1H), 1.60-1.44 (m, 4H), 1.38 (d, J= 7.2 Hz, 3H), 1.32-1.23 (m, 2H), 0.93 (s, 9H) 204 I-2162-[[(2S,11S)-2-[[(2S)-4- 1246.40 (400 MHz, DMSO-d₆) δ 12.10 (s, 1H),9.01-8.94 carbamoyl-1-[3-fluoro-5-(5-[[(2S)- (m, 2H), 8.83 (s, 1H), 8.37(d, J = 7.8 Hz, 1H), 1-[(2S,4R)-4-hydroxy-2-[[(1S)- 8.17-8.08 (m, 1H),8.00-7.93 (m, 1H), 7.80 (d, J = 1-[4-(4-methyl-1,3-thiazol-5- 9.3 Hz,1H), 7.54 (d, J = 8.8 Hz, 1H), 7.49 (d, yl)phenyl]ethyl]carbamoyl] J =2.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d,pyrrolidin-1-yl]-3,3-dimethyl-1- J = 8.3 Hz, 2H), 7.25 (s, 1H),7.13-7.08 (m, 2H), oxobutan-2-yl]carbamoyl]pentyl) 7.02-6.98 (m, 1H),6.75 (s, 1H), 6.65-6.57 (m, phenoxy]butan-2-yl]carbamoyl]- 3H),5.11-5.08 (m, 1H), 4.94-4.90 (m, 1H), 4.75- 12-oxo-1-azatricyclo 4.66(m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.45-4.42 [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13),5, (m, 1H), 4.29 (s, 1H), 4.08-3.83 (m, 4H),3.64- 7-trien-11-yl]carbamoyl]-1H- 3.60 (m, 2H), 3.48-3.44 (m, 1H),3.30-3.02 (m, indole-5-carbonylphosphonic 3H), 2.89-2.85 (m, 1H), 2.53(s, 1H), 2.46 (s, acid 3H), 2.34-2.19 (m, 3H), 2.18-2.06 (m, 4H), 2.05-2.01 (m, 1H), 1.92-1.75 (m, 2H), 1.75-1.63 (m, 1H), 1.62-1.45 (m, 5H),1.38 (d, J = 7.1 Hz, 3H), 1.29-1.25 (m, 2H), 0.94 (s, 9H) 205 I-2172-[[(2S,11S)-2-[[(2S)-4- [(M + (300 MHz, DMSO-d₆) δ 12.01 (s, 1H),9.04-8.82 carbamoyl-1-[2-fluoro-3-(5-[[(2S)- 1)]⁺ = (m, 3H), 8.35 (d, J= 7.8 Hz, 1H), 8.12 (d, J = 6.6 1-[(2S,4R)-4-hydroxy-2-[[(1S)- 1246.36Hz, 1H), 8.02-7.93 (m, 1H), 7.77 (d, J = 9.2 Hz,1-[4-(4-methyl-1,3-thiazol-5- 1H), 7.59-7.29 (m, 6H), 7.24 (s, 1H),7.13-6.91 yl)phenyl]ethyl]carbamoyl] (m, 5H), 6.82-6.73 (m, 2H),5.09-5.06 (m, 1H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.99-4.83 (m, 1H),4.74-4.62 (m, 1H), 4.51 (d, J = oxobutan-2-yl]carbamoyl] 9.3 Hz, 1H),4.43-4.41 (m, 1H), 4.29-4.26 (m, pentyl)phenoxy]butan-2-yl] 1H),4.04-3.89 (m, 3H), 3.64-3.35 (m, 5H), 3.18-carbamoyl]-12-oxo-1-azatricyclo 3.13 (m, 2H), 2.94-2.82 (m, 1H),2.59-2.50 (m, [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5, 4H),2.45 (s, 3H), 2.13-2.09 (m, 6H), 1.86-1.65 7-trien-11-yl]carbamoyl]-1H-(m, 3H), 1.58-1.42 (m, 4H), 1.38 (d, J = 6.8 Hz,indole-5-carbonylphosphonic 3H), 1.29-1.25 (m, 2H), 0.92 (s, 9H) acid206 I-218 diammonium 2-[[(2S,11S)-2- 1256.25 (400 MHz, DMSO-d₆) δ 11.90(s, 1H), 8.99 (s, [[(3S,4R)-1-carbamoyl-4-[[4- 1H), 8.97-8.84 (m, 2H),8.39 (d, J = 7.8 Hz, 1H), (4-[[(2S)-1-[(2S,4R)-4-hydroxy- 7.95 (dd, J =8.8, 1.6 Hz, 1H), 7.88-7.85 (m, 2H), 2-[[(1S)-1-[4-(4-methyl-1,3-7.47-7.35 (m, 6H), 7.18 (s, 1H), 7.14-6.95 (m,thiazol-5-yl)phenyl]ethyl] 6H), 6.69 (s, 1H), 5.12-5.08 (m, 1H),4.96-4.89 carbamoyl]pyrrolidin-1-yl]-3,3- (m, 1H), 4.70-4.67 (m, 1H),4.53 (d, J = 9.3 Hz, dimethyl-1-oxobutan-2-yl] 1H), 4.45-4.43 (m, 1H),4.37-4.35 (m, 2H), 4.28,3-d carbamoyl]butyl)-3-methylphenyl] (s, 1H),3.82-3.74 (m, 1H), 3.65-3.58 (m, 2H), methoxy]pentan-3-yl]carbamoyl]-3.51-3.42 (m, 3H), 3.22-3.07 (m, 3H), 2.89 (d, J = 12-oxo-1-azatricyclo16.7 Hz, 1H), 2.46 (s, 3H), 2.35-2.32 (m, 3H), [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13),5,7- 2.32-2.11 (m, 5H), 2.10-1.95 (m, 3H),1.83-1.75 trien-11-yl]carbamoyl]-1H- (m, 3H), 1.60-1.44 (m, 6H), 1.38(d, J = 7.0 Hz, indole-5-carbonylphosphonate 3H), 1.10 (d, J = 6.1 Hz,3H), 0.94 (s, 9H) 207 I-219 2-[[(2S,11S)-2-[[(3S,4R)-1- 1242.45 (400MHz, DMSO-d₆) δ 12.06 (s, 1H), 9.02-8.94carbamoyl-4-[3-(5-[[(2S)-1-[(2S, (m, 2H), 8.85 (s, 1H), 8.38 (d, J = 7.8Hz, 1H), 4R)-4-hydroxy-2-[[(1S)-1-[4- 8.04-7.93 (m, 2H), 7.81 (d, J =9.2 Hz, 1H), 7.48- (4-methyl-1,3-thiazol-5-yl) 7.41 (m, 3H), 7.39-7.37(m, 2H), 7.22 (s, 1H), phenyl]ethyl]carbamoyl]pyrrolidin- 7.15-7.02 (m,3H), 6.99-6.96 (m, 1H), 6.74 (d, J = 1-yl]-3,3-dimethyl-1- 7.8 Hz, 2H),6.67-6.66 (m, 2H), 5.12-5.08 (m, oxobutan-2-yl]carbamoyl]pentyl) 2H),4.96-4.89 (m, 1H), 4.73-4.64 (m, 1H), 4.52 .phenoxy]pentan-3-yl]carbamoyl]- (d, J = 9.3 Hz, 1H), 4.46-4.34 (m, 2H),4.28 (s, 12-oxo-1-azatricyclo 1H), 3.86-3.80 (m, 1H), 3.65-3.58 (m, 2H),3.47- [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5,7- 3.43 (m,2H), 3.22-3.10 (m, 3H), 2.79 (d, J = 16.6trien-11-yl]carbamoyl]-1H-indole- Hz, 1H), 2.68-2.65 (m, 1H), 2.46 (s,3H), 2.29- 5-carbonylphosphonic acid 2.21 (m, 4H), 2.16-1.97 (m, 5H),1.94-1.73 (m, 2H), 1.71-1.41 (m, 6H), 1.38 (d, J = 7.0 Hz, 3H),1.30-1.24 (m, 2H), 1.18 (d, J = 6.1 Hz, 3H), 0.93 (s, 9H). 208 I-2202-[[(2S,11S)-2-[[(1S)-3- 1255.55 (400 MHz, CD₃OD) δ 9.00 (d, J = 14.3Hz, 1H), carbamoyl-1-([[3-(5[[(2S)-1-[(2S, 8.84 (s, 1H), 8.05 (dd, J =15.9, 8.2 Hz, 1H), 7.54 4R)-4-hydroxy-2-[[(1S)-1-[4- (d, J = 8.6 Hz,1H), 7.42-7.37 (m, 4H), 7.36-7.34 (4-methyl-1,3-thiazol-5-yl) (m, 1H),7.18-6.95 (m, 7H), 5.21-5.19 (m, 1H), phenyl]ethyl]carbamoyl] 4.97 (d, J= 7.0 Hz, 1H), 4.78-4.76 (m, 1H), 4.63- pyrrolidin-1-yl]-3,3-dimethyl-1-4.54 (m, 2H), 4.40-4.38 (m, 2H), 4.35-4.30 (m,oxobutan-2-yl]carbamoyl]pentyl) 2H), 3.87 (d, JJ = 11.0 Hz, 1H), 3.73(dd, J = phenyl]methyl]carbamoyl)propyl] 11.0, 3.8 Hz, 1H), 3.62-3.51(m,2H), 3.23-3.21 carbamoyl]-12-oxo-1-azatricyclo (m, 2H), 3.14-3.05 (m,1H), 2.53-2.50 (m, 2H), [6.4.1.0{circumflex over ( )}[4,13]]trideca-42.45 (s, 3H), 2.34-2.28 (m, 3H), 2.25-2.07 (m,(13),5,7-trien-11-yl]carbamoyl]- 4H), 2.03-1.96 (m, 2H), 1.60-1.51 (m,4H), 1.47 1H-indole-5- (d, J = 7.0 Hz, 3H), 1.29-1.21 (m, 2H), 1.02 (s,carbonylphosphonic acid 9H). 209 I-221 diammonium 2-(2S,11S)-2- 1200.75(400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 8.99 (s, [(2S)-4-carbamoyl-1-[3-(41H), 8.95 (d, J = 8.1 Hz, 1H), 8.87 (s, 1H), 8.57-[[(2S)-1-[(2S,4R)-4-hydroxy-2- 8.55 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H),7.94 (dd, ([[4-(4-methyl-1,3-thiazo1-5-yl) J = 8.8, 1.6 Hz, 1H), 7.87(d, J = 9.3 Hz, 1H), phenyl]methyl]carbamoyl) 7.48-7.38 (m, 6H), 7.24(s, 1H), 7.17 (dd, J = 8.9, pyrrolidin-1-yl]-3,3-dimethyl-1- 7.3 Hz,1H), 7.11-7.08 (m, 2H), 7.01-6.98 (m, oxobutan-2-yl]carbamoyl]butyl 1H),6.79-6.69 (m, 4H), 5.10-5.08 (m, 2H), 4.72-phenoxy]butan-2-yl]carbamoyl]- 4.66 (m, 1H), 4.55 (d, J = 9.3 Hz, 1H),4.47-4.39 12-oxo-1-azatricyclo (m, 2H), 4.35 (s, 1H), 4.22 (dd, J =15.8, 5.4 Hz, [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5, 1H),4.02-3.96 (m, 1H), 3.93-3.86 (m, 3H), 3.71- 7-trien-11-yl]carbamoyl]-1H-3.61 (m, 3H), 3.51-3.40 (m, 1H), 3.16-3.09 (m,indole-5-carbonylphosphonate 1H), 2.88 (d, J = 16.6 Hz, 1H), 2.69-2.67(m, 1H), 2.45 (s, 3H), 2.35-2.33 (m, 1H), 2.31-1.99 (m, 7H), 1.96-1.62(m, 3H), 1.60-1.47 (m, 5H), 0.94 (s, 9H). 210 I-2222-[[(2S,11S)-2-[[(1S)-3- 1241.55 (400 MHz, CD₃OD) δ 8.94 (s, 1H), 8.88(s, 1H), carbamoyl-1--([[3-(5-[[(2S)-1-[(2S, 8.07(d, J = 8.8 Hz, 1H),7.56 (d, J = 8.6 Hz, 1H), 4R)-4-hydroxy-2-([[4-(4- 7.47-7.43 (m, 2H),7.39 (d, J = 8.2 Hz, 2H), 7.34 methyl-1,3-thiazol-5-yl)phenyl] (s, 1H),7.13 (d, J = 7.6 Hz, 3H), 7.09-6.98 (m, me thyl]carbamoyl)pyrrolidin-1-4H), 5.21(dd, J = 10.8, 3.5 Hz, 1H), 4.79 (d, J =yl]-3,3-dimethyl-1-oxobutan-2- 7.4 Hz, 1H), 4.66 (s, 1H), 4.63-4.48 (m,3H), yl]carbamoyl]pentyl)phenyl] 4.43-4.39 (m, 1H), 4.37-4.31 (m, 3H),3.92 (d, J = methyl]carbamoyl)propyl] 11.1 Hz, 1H), 3.81(dd, J = 11.1,3.9 Hz, 1H), carbamoyl]-12-oxo-1-azatricyclo 3.54 (d, J = 5.5 Hz, 1H),3.26-3.22 (m, 2H), 3.13- [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13), 3.09 (m, 1H), 2.54-2.50 (m, 2H), 2.49-2.45 (m,5,7-trien-11-yl]carbamoyl]-1H- 3H), 2.39-2.34 (m, 1H), 2.33-2.29 (m,3H), 2.27- indole-5-carbonylphosphonic 2.19 (m, 3H), 2.15-1.97(m, 3H),1.60-1.55 (m, acid 4H),1.33-1.23 (m, 2H), 1.04 (s, 9H) 212 I-223diammonium 2-[[(2S,11S)-2- 1255.65 (400 MHz, DMSO-d₆) δ 11.86 (s, 1H),8.99-8.96 [[(3S,4R)-1-carbamoyl-4-([4- (m, 2H), 8.59 (s, 1H), 7.95-7.86(m, 1H), 7.42- [3-(1-[[(2S)-1-[(2S,4R)-4- 7.39 (m, 7H), 7.16-6.95 (m,9H), 6.75-6.69 (m, hydroxy-2-([[4-(4-methyl-1,3- 2H), 5.14-5.10 (m, 1H),4.67 (s, 1H), 4.54 (d, J = thiazol-5-yl)phenyl]methyl] 8.9 Hz, 1H),4.48-4.44 (m, 1H), 4.43-4.32 (m, carbamoyl)pyrrolidin-1-yl]-3,3- 3H),4.30-4.20 (m, 1H), 3.83-3.77 (m, 1H), 3.65- dimethyl-1-oxobutan-2-yl]3.57 (m, 2H), 3.48-3.40 (m, 3H), 3.20-3.03 (m,carbamoyl]cyclopropyl)propyl] 2H), 2.88-2.84 (m, 1H), 2.43-2.41 (m, 4H),2.30- phenyl]methoxy)pentan-3-yl] 2.14 (m, 2H), 2.06-2.14 (m, 3H),1.93-1.87 (m, carbamoyl]-12-oxo-1-azatricyclo 1H), 1.74-1.70 (m, 4H),1.45-1.40 (m, 3H), 1.24 [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13),5, (s, 1H), 1.08-1.04 (m, 3H), 0.97 (s, 9H),0.89- 7-trien-11-yl]carbamoyl]-1H- 0.81 (m, 4H), 0.62-0.48 (m, 2H)indole-5-carbonylphosphonate 213 I-224 diammonium 2-[[(2S,11S)-2-1212.40 (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 9.01-8.88[[(3R)-1-carbamoyl-5-[3-[5- (m, 3H), 8.60-8.56 (m, 1H), 8.00-7.90 (m,2H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.85 (d, J = 9.3 Hz, 1H), 7.45-7.37(m, 6H), 7.21 ([[4-(4-methyl-1,3-thiazo1-5-yl) (s, 1H), 7.14-7.10 (m,3H), 7.02-6.93 (m, 4H), phenyl]methyl]carbamoyl) 6.71 (s, 1H), 5.08 (dd,J = 10.7, 2.9 Hz, 1H), 4.74- pyrrolidin-1-yl]-3,3-dimethyl-1- 4.64 (m,1H), 4.58-4.51 (m, 1H), 4.48-4.38 (m, oxobutan-2-yl]carbamoyl]pentyl)2H), 4.38-4.33 (m, 1H), 4.23 (dd, J = 15.8, 5.4 phenyl]pentan-3-yl]carbamoyl]- Hz, 1H), 3.69 (m, 4H), 3.58-3.43 (m, 4H), 3.23-12-oxo-1-azatricyclo 3.07 (m, 3H), 2.95 (d, J = 16.7 Hz, 1H), 2.50-2.46[6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),5, (m, 2H), 2.45 (s,3H), 2.32-2.20 (m, 3H), 2.17- 7-trien-11-yl]carbamoyl]-1H- 2.00 (m, 4H),1.96-1.85 (m, 1H), 1.70-1.58 (m, indole-5-carbonylphosphonate 4H),1.57-1.44 (m, 4H), 1.31-1.21 (m, 2H), 0.94 (s, 9H) 215 I-225 diammonium2-[[(2S,11S)-2- 1261.90 (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.01-8.85[[(3S,4R)-1-carbamoyl-4-[[2- (m, 3H), 8.39 (d, J = 7.8 Hz, 1H),7.99-7.81 (m, fluoro-4-(4-[[(2S)-1-[(2S,4R)-4- 3H), 7.47-7.35 (m, 6H),7.28-7.24 (m, 1H), 7.20- hydroxy-2-[[(1S)-1-[4-(4- 6.89 (m, 6H), 6.69(s, 1H), 5.11 (dd, J = 10.7, 2.9 methyl-1,3-thiazol-5-yl)phenyl] Hz,1H), 4.96-4.89 (m, 1H), 4.70-4.65 (m, 1H),ethyl]carbamoyl]pyrrolidin-1-yl]- 4.56-4.37 (m, 4H), 4.28 (s, 1H),3.78-374 (m, 3,3-dimethyl-1-oxobutan-2- 1H), 3.64-3.58 (m, 2H),3.49-3.44 (m, 3H), 3.22- yl]carbamoyl]butyl)phenyl] 3.04 (m, 2H), 2.89(d, J = 16.6 Hz, 1H), 2.60-2.55 methoxy]pentan-3-yl]carbamoyl]- (m, 2H),2.46 (s, 3H), 2.38-1.93 (m, 6H), 1.84- 12-oxo-1-azatricyclo 1.74(m, 2H),1.61-1.42 (m, 8H), 1.38 (d, J = 6.9 [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13),5,7- Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H), 0.94(s, 9H) trien-11-yl]carbamoyl]-1H-indole- 5-carbonylphosphonate 216I-226 2-[[(2S,11S)-2-[[(3S,4R)-1- 1256.75 (400 MHz, CD₃OD) δ 8.98-8.84(m, 2H), 8.13- carbamoyl-4-[[4-(4-[[(2S)-1-[(2S, 7.89 (m, 1H), 7.59-7.30(m, 6H), 7.21-6.97(m, 4R)-4-hydroxy-2-[[(1S)-1- 5H), 6.93-6.90 (m, 1H),5.18 (dd, J = 10.8, 3.3 [4-(4-methyl-1,3-thiazol-5-yl) Hz, 1H),5.02-5.00 (m, 1H), 4.81-4.79 (m, 1H), phenyl]ethyl]carbamoyl]pyrrolidin-4.65-4.40 (m, 5H), 4.03-3.99 (m, 1H), 3.89 (d, J = 1-yl]-3,3-dimethyl-1-11.1 Hz, 1H), 3.76 (dd, J = 11.0, 4.0 Hz, 1H),oxobutan-2-yl]carbamoyl]butyl)- 3.64-3.57 (m, 1H), 3.55-3.46 (m, 1H),3.25-3.23 2-methylphenyl]methoxy] (m, 2H), 3.09-3.05 (m, 1H), 2.57-5.54(m, 2H), pentan-3-yl]carbamoyl]-12-oxo- 2.49 (d, J = 1.3 Hz, 3H),2.45-2.16 (m, 10H), 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]2.06-1.92 (m, 2H), 1.65 (d, J = 25.1 Hz, 5H), 1.51trideca-4(13),5,7-trien-11-yl] (d, J = 7.0 Hz, 3H), 1.22 (d, J = 6.3 Hz,3H), 1.05 carbamoyl]-1H-indole-5- (s, 9H) carbonylphosphonic acid 217I-227 2-[[(2S,11S)-2-[[(3S,4R)-1- 1230.35 (400 MHz, CD₃OD) δ 8.93 (s,1H), δ 8.86 (s, 1H), carbamoyl-4-[[4-(4-[[(2S)-1- 8.08 (d, J = 9.4 Hz,1H), 8.00 (d, J = 9.4 Hz, 1H), [(2S,4R)-4-hydroxy-2-[[4-(4- 7.51 (d, J =8.8 Hz, 1H), 7.41 ? 7.28 (m, 4H), methyl-1,3-thi azol-5-yl)phenoxy] 7.22(d, J = 7.7 Hz, 2H), 7.15-7.03 (m, 5H), 5.19carbamoyl]pyrrolidin-1-yl]-3, (dd, J = 10.9, 3.3 Hz, 1H), 4.65-4.48 (m,5H), 3-dimethyl-1-oxobutan-2-yl] 4.06-3.92 (m, 2H), 3.83 (dd, J = 10.8,3.9 Hz, carbamoyl]butyl)phenyl] 1H), 3.64-3.46(m, 4H), 3.23-3.21 (m,2H), 3.09- methoxylpentan-3-yl]carbamoyl]- 3.05 (m, 2H), 2.63-2.57 (m,2H), 2.46 (s, 3H), 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}2.36-2.25 (m, 4H), 1.96(s, 1H), 1.68-1.55 (m,[4,13]]trideca-4(13),5,7-trien- 5H), 1.40-1.31 (m, 2H), 1.20(d, J = 6.3Hz, 3H), 11-yl]carbamoyl]-1H-indole-5- 1.05 (s, 9H) carbonylphosphonicacid 218 I-228 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1153.65 (400 MHz, DMSO-d₆) δ12.16-11.95 (m, 1H), carbamoyl-1- 11.25 (s, 1H), 8.85-8.75 (m, 2H),8.51-8.13 (m, (diphenylmethylcarbamoyl) 2H), 7.98-7.96 (m, 1H),7.58-7.53 (m, 2H), 7.41- propyl]carbamoyl]- 7.19 (m, 11H), 7.09-7.07 (m,1H), 6.99-6.73 (m, 3-(4-[3-[1-(2,6-dioxopiperidin- 4H), 6.19-5.99 (m,1H), 5.34-5.30 (m, 1H), 5.05- 3-yl)-3-methyl-2-oxo-1,3- 4.95 (m, 1H),4.63-4.55 (m, 2H), 4.23-4.19 (m, benzodiazol-5-yl]cyclobutyl] 1H),4.18-4.11 (m, 1H), 4.05-3.99 (m, 1H), 3.95-butanoyl)-6-oxo-octahydropyrrolo 3.90 (m, 1H), 3.87-3.77 (m, 2H),3.75-3.62 (m, [1,2-a][1,5]diazocin-5-yl] 2H), 3.62-3.53 (m, 1H),2.95-2.62 (m, 4H), 2.60- carbamoyl]-1H-indole-5- 2.55 (m, 2H), 2.45-2.38(m, 2H), 2.22-1.95 (m, carbonylphosphonic acid 8H), 1.94-1.73 (m, 3H),1.67-1.58 (m, 4H), 1.45- 1.37 (m, 2H), 1.35-1.11 (m, 1H) 219 I-2292-[[(2S,11S)-2-[[(1S)-3-carbamoyl- 1132.20 (400 MHz, DMSO-d₆) δ 12.07(s, 1H), 11.09 (s, 1-(diphenylmethylcarbamoyl) 1H), 8.93 (d, J = 7.8 Hz,1H), 8.86-8.74 (m, 2H), propyl]carbamoyl]-6-[6- 8.22 (d, J = 7.9 Hz,1H), 7.95 (d, J = 8.7 Hz, 1H), [1-(2,6-dioxopiperidin-3-yl)- 7.51 (d, J= 8.7 Hz, 1H), 7.48-7.41 (m, 1H), 7.36- 3-methyl-2-oxo-1,3-benzodiazol-7.16 (m, 13H), 7.07-6.96 (m, 2H), 6.94-6.84 (m,5-yl]hexyl]-12-oxo-1-azatricyclo 3H), 6.77 (s, 1H), 6.07 (d, J = 8.3 Hz,1H), 5.34 [6.4.1.0 [4,13]]-trideca- (dd, J = 12.7, 5.4 Hz, 1H),5.17-5.06 (m, 1H), 4(13),5,7-trien-11-yl]carbamoyl]- 4.67-4.63 (m, 1H),4.34-4.30 (m, 1H), 3.45-3.36 1H-indole-5- (m, 3H), 3.32 (s, 3H),3.20-3.01 (m, 1H), 2.97- carbonylphosphonic acid 2.82 (m, 2H), 2.77-2.66(m, 2H), 2.66-2.56 (m, 3H), 2.28-2.14 (m, 2H), 2.14-1.95 (m, 2H), 1.95-1.86 (m, 1H), 1.84-1.68 (m, 1H), 1.68-1.48 (m, 4H), 1.37-1.34 (m, 5H)220 I-230 2-[[(5S,8S,10aR)-8-[[(1R)-3- 1169.50 (400 MHz, DMSO-d₆) δ12.03-11.96 (m, 1H), carbamoyl-1-[[(4- 11.21-10.76 (m, 1H), 8.87-8.82(m, 1H), 8.67- methanesulfonylphenyl)methyl] 8.31 (m, 2H), 8.28-8.24 (m,1H), 8.03-7.94 (m, carbamoyl]propyl]carbamoyl]-6-oxo-3- 1H), 7.82-7.74(m 1H), 7.58-7.49 (m, 2H), 7.44- [2-[(1S,4S)-4-[[1-(2,6- 7.04 (m, 4H),7.03-6.91 (m, 1H), 6.89-6.71 (m, dioxopiperidin-3-yl)-3-methyl-2-oxo-2H), 5.38-5.29 (m, 1H), 5.07-4.74 (m, 1H), 4.53-1,3-benzodiazol-5-yl]methyl] 4.42 (m, 2H), 4.29-4.16 (m, 2H), 3.95-3.62(m, cyclohexyl]acetyl]- 2H), 3.33 (s, 3H), 3.28-3.15 (m, 6H), 3.15-3.04octahydropyrrolo[1,2-a][1,5]diazocin- (m, 2H), 2.97-2.84 (m, 1H),2.77-2.53 (m, 6H), 5-yl]carbamoyl]-1H-indole-5- 2.41-2.27 (m, 1H),2.26-2.19 (m, 2H), 2.18-2.09 carbonylphosphonic acid (m, 3H), 2.08-1.83(m, 5H), 1.78-1.72 (m, 3H), 1.48-1.39 (m, 8H) 221 I-231 diammonium2-[[(5S,8S,10aR)- [(M − (400 MHz, DMSO-d₆) δ 9.01-8.97 (m, 1H), 8.93-3-acetyl-8-[[(2S)-4-carbamoyl- 1)]⁻ = 8.90 (m, 1H), 8.49-8.47 (m, 1H)8.39 (d, J = 7.8 1-[2-fluoro-3-(3[[(2S)-1- 1239.95 Hz, 1H), 8.09-8.02(m, 1H), 7.95 (d, J = 8.7 Hz, [(2S,4R)-4-hydroxy-2-[[(1S)-1- 1H), 7.88(d, J = 9.0 Hz, 1H), 7.46-7.34 (m, 6H), [4-(4-methyl-1,3-thiazo1-5-yl)7.29-7.23 (m, 1H), 7.06-6.98 (m, 2H), 6.81-6.67phenyl]ethyl]carbamoyl]pyrrolidin- (m, 3H), 5.05-5.02 (m, 1H), 4.93-4.91(m, 1H), 1-yl]-3,3-dimethyl-1- 4.53 (d, J = 9.3 Hz, 1H), 4.46-4.36 (m,2H), 4.31- oxobutan-2-yl]carbamoyl]propyl) 5.27 (m, 2H), 4.03-3.85 (m,4H), 3.71-3.69 (m, phenoxy]butan-2-yl]carbamoyl]- 2H), 3.62-3.60 (m,2H), 3.49-3.41 (m, 3H) 2.59- 6-oxo-octahydropyrrolo 2.56 (m, 3H), 2.47(s, 3H), 2.28-2.11 (m, 8H), [1,2-a][1,5]diazocin-5-yl] 2.06-2.01 (m,2H), 1.91-1.65 (m, 9H), 1.38 (d, J = carbamoyl]-1H-indole-5- 7.0 Hz,3H), 0.95 (s, 9H) carbonylphosphonate 222 I-2322-[[(2S,11S)-2-[[(1S)-3-carbamoyl- 1098.45 (400 MHz, DMSO-d₆) δ 12.07(s, 1H), 11.09 (s, 1-[[(4-isopropylphenyl) 1H), 9.01-8.93 (m, 1H), 8.83(s, 1H), 8.36-8.32 methyl]carbamoyl]propyl] (m, 1H), 8.26 (d, J = 7.8Hz, 1H), 7.96 (d, J = 8.7 carbamoyl]-6-[6-[1-(2,6- Hz, 1H), 7.52 (d, J =8.8 Hz, 1H), 7.47 (s, 1H), dioxopiperidin-3-yl)-3-methyl-2-oxo- 7.28 (s,1H), 7.14-7.09 (m, 4H), 7.05-6.98 (m, 1,3-benzodiazol-5-yl]hexyl]- 2H),6.95-6.84 (m, 3H), 6.78 (s, 1H), 5.34 (m,12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} 1H), 5.13 (m, 1H),4.67 (t, J = 10.4 Hz, 1H),4.26- [4,13]]trideca-4(13),5,7-trien- 4.13 (m,3H), 3.48-3.37 (m, 3H), 3.48-3.27 (m, 11-yl]carbamoyl]-1H-indole- 3H),3.20-3.04 (m, 3H), 2.98-2.89 (m, 2H), 2.87- 5-carbonylphosphonic acid2.78 (m, 2H), 2.74-2.57 (m, 4H), 2.24-2.18 (m, 2H), 2.13-2.04 (m, 2H),2.02-1.97 (m, 1H), 1.90 (m, 1H), 1.79 (m, 1H), 1.64-1.52 (m, 4H), 1.39-1.31 (m, 4H), 1.16 (d, J = 6.9 Hz, 6H) 223 I-233 diammonium2-[[(5S,8S,10aR)- 1271.50 (400 MHz, DMSO-d₆) δ 12.02-11.82 (m, 1H),3-acetyl-8-[[(2S)-4-carbamoyl- 8.99 (s, 1H), 8.89 (s, 1H), 8.49 (d, J =6.9 Hz, 1-[2-chloro-3-(4-[[(2S)-1- 1H), 8.39 (d, J = 7.8 Hz, 1H),8.09-8.01 (m, 1H), [(2S,4R)-4-hydroxy-2-[[(1S)-1- 7.99-7.92 (m, 1H),7.84 (d, J = 9.2 Hz, 1H), 7.47- [4-(4-methyl-1,3-thiazol-5-yl) 7.37 (m,5H), 7.37-7.30 (m, 1H), 7.28 (s, 1H), phenyl]ethyl]carbamoyl]pyrrolidin-7.24-7.15 (m, 1H), 7.01-6.97 (m, 1H), 6.93-6.89 1-yl]-3,3-dimethyl-1- (m1H) 6.81 (s, 1H), 5.06-5.00 (m, 1H), 4.95-oxobutan-2-yl]carbamoyl]butyl) 4.89 (m, 1H), 4.52 (d, J = 9.3 Hz, 1H),4.47-4.33 phenoxy]butan-2-yl]carbamoyl]- (m, 2H), 4.30-4.25 (m, 2H),4.11-4.00 (m, 2H), 6-oxo-octahydropyrrolo 3.97-3.83 (m, 2H), 3.72-3.68(m, 2H), 3.64-3.58 [l,2-a][1,5]diazocin-5-yl]carbamoyl]- (m, 2H),3.45-3.29 (m, 2H), 2.71-2.67 (m, 2H), 1H-indole-5-carbonylphosphonate2.46 (s, 3H), 2.33-2.28 (m, 1H), 2.28-2.21 (m, 4H), 2.20-2.11 (m, 3H),2.09-1.97 (m, 2H), 1.97- 1.84 (m, 3H), 1.83-1.65 (m, 4H), 1.62-1.45 (m,6H), 1.38 (d, J = 7.0 Hz, 3H), 0.94 (s, 9H) 224 I-237 diammonium2-[[(2S,11S)-2- 1226.55 (300 MHz, DMSO-d₆) δ 11.84 (s, 1H), 9.03-8.90[[(3R)-1-carbamoyl-6-[4-(4- (m, 3H), 8.49-8.37 (m, 1H), 8.06-7.71 (m,3H), [[(2S)-1-[(2S,4R)-4-hydroxy-2- 7.50-7.33 (m, 6H), 7.28-6.94 (m,8H), 6.72 (s, [[(1S)-1-[4-(4-methyl-1,3-thiazol- 1H), 5.11-5.01 (m, 1H),4.99-4.88 (m, 1H), 4.75- 5-yl)phenyl]ethyl]carbamoyl] 4.69 (m, 1H),4.58-4.39 (m, 2H), 4.31-1.27 (m, pyrrolidin-1-yl]-3,3-dimethyl- 1H),3.80-3.44 (m, 4H), 3.43-3.23 (m, 5 H), 3.20- 1-oxobutan-2-yl]carbamoyl]3.07 (m, 3H), 2.94-2.70 (m, 1H), 2.47 (s, 3H), butyl)phenyl]hexan-3-yl]2.33-2.14 (m, 3H), 2.09-1.96 (m, 3H), 1.88-1.70carbamoyl]-12-oxo-1-azatricyclo (m, 1H), 1.69-1.44(m, 12H), 1.38 (d, J =7.0 Hz, [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13), 3H), 0.95 (s,9H) 5,7-trien-11-yl]carbamoyl]-1H- indole-5-carbonylphosphonate 225I-238 diammonium 2-[[(2S,11S)-2- 1199.50 (300 MHz, DMSO-d₆) δ 12.08 (s,1H), 9.02-8.95 [[(1S)-3-carbamoyl-1-[5-(5- (m, 1H), 8.93-8.88 (m, 1H),8.69 (d, J = 7.7 Hz, [[(2S)-1-[(2S,4R)-4-hydroxy-2- 2H), 8.42 (d, J =7.7 Hz, 1H), 8.38-8.33 (m, 1H), [(1S)-1-[4-(4-methyl-1,3- 7.97 (d, J =8.7 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), thiazol-5-yl)phenyl]ethyl]7.61-7.54 (m, 1H), 7.46-7.37 (m, 6H), 7.34-7.27carbamoyl]pyrrolidin-1-yl]-3,3- (m, 1H), 7.19 (d, J = 8.0 Hz, 1H),7.08-7.05 (m, dimethyl-1-oxobutan-2-yl]carbamoyl] 2H), 7.01-6.90 (m,1H), 6.78 (s, 1H), 5.17-5.06 pentyl)pyridin-2-yl]propyl] (m, 1H),4.94-4.89 (m, 1H), 4.70-4.67 (m, 2H), carbamoyl]-12-oxo-1-azatricyclo4.53-4.50 (d, J = 9.2 Hz, 1H), 4.46-4.43 (m, 1H), [6.4.1.0{circumflexover ( )}[4,13]]trideca-4(13), 4.30-4.28 (m, 1H), 3.61-3.60 (m, 3H),3.52-3.43 5,7-trien-11-yl]carbamoyl]- (m, 1H), 3.16-3.10 (m, 2H),2.81-2.61 (m, 3H), 1H-indole-5-carbonylphosphonate 2.46 (s, 3H),2.32-1.17 (m, 4H), 2.16-1.98 (m, 4H), 1.96-1.72 (m, 4H), 1.68-1.44 (m,4H), 1.39- 1.36 (d, J = 7.0 Hz, 3H), 1.31-1.24 (m, 2H), 0.93 (s, 9H) 226I-239 diammonium 2-[[(2S)-1-[(2S)- 1231.40 (400 MHz, DMSO-d₆) δ 11.88(s, 1H), 8.99 (s, 2-[[(2S)-4-carbamoyl-1-[2- 1H), 8.93-8.83 (m, 1H),8.76 (d, J = 7.9 Hz, 1H), chloro-3-(4-[[(2S)-1-[(2S,4R)- 8.42 (d, J =7.9 Hz, 1H), 7.99-7.93 (m, 1H), 7.92- 4-hydroxy-2-[[(1S)-1-[4-(4- 7.83(m, 2H), 7.48-7.30 (m, 6H), 7.25-7.16 (m,methyl-1,3-thiazol-5-yl)phenyl] 2H), 7.03-6.95 (m, 1H), 6.95-6.89 (m,1H), 6.83- ethyl]carbamoyl]pyrrolidin-1- 6.78 (m, 1H), 4.96-4.88 (m,1H), 4.87-4.83 (m, yl]-3,3-dimethyl-1-oxobutan- 1H), 4.55-4.50 (m, 1H),4.48-4.40 (m, 1H), 4.37- 2-yl]carbamoyl]butyl)phenoxy] 4.30 (m, 1H),4.30-4.26 (m, 1H), 4.09-4.05 (m, butan-2-yl]carbamoyl] 1H), 4.00-3.89(m, 2H), 3.88-3.79 (m, 1H), 3.66- pyrrolidin-1-yl]-4-methyl-1- 3.55 (m,4H), 3.50-3.30 (m, 1H), 2.71-2.67 (m, oxopentan-2-yl]carbamoyl]-1H- 3H),2.46 (s, 3H), 2.33-2.29 (m, 1H), 2.24-2.11 indole-5-carbonylphosphonate(m, 3H), 2.07-2.03 (m, 2H), 1.95-1.78 (m, 3H), 1.77-1.66 (m, 4H),1.56-1.52 (m, 6H), 1.38 (d, J = 7.0 Hz, 3H), 1.02-0.88 (m, 15H) 227I-240 2-[[(2S)-1-[(2S)-2-[[(2S)-4- 1216.45 (400 MHz, DMSO-d₆) δ11.86-11.67 (m, 1H), carbamoyl-1-[2-chloro-3-(3-[[(2 10.16-10.00 (m,1H), 8.99 (s, 1H), 8.93-8.88 (m, S)-1-[(2S,4R)-4-hydroxy-2- 1H), 8.73(d, J = 8.0 Hz, 1H), 8.41 (d, J = 7.7 Hz,[[(1S)-1-[4-(4-methyl-1,3-thiazol- 1H), 8.00-7.83 (m, 3H), 7.44-7.37 (m,5H), 7.24- 5-yl)phenyl]ethyl]carbamoyl- 7.17 (m, 2H), 6.99 (d, J = 8.2Hz, 1H), 6.89 (d, J = pyrrolidin-1-yl]-3,3-dimethyl- 7.7 Hz, 1H), 6.79(s, 1H), 4.98-4.90 (m, 2H), 1-oxobutan-2-yl]carbamoyl] 4.54 (d, J = 9.1Hz, IH), 4.45-4.41 (m, IH), 4.37- propyl)phenoxy]butan-2-yl] 4.24 (m 2H)4 07-4 05 (m 1H) 3.97-3.92 (m carbamoyl]pyrrolidin-1-yl]-4- 2H),3.8,3-3.7,9 (m. , 1H), 3.63-3.60 (m, 2H), 3.55: methyl-1-oxopentan-2-yl]3.51 (m, 1H), 3.47-3.43 (m, 2H), 3.23-3.20 (m, carbamoyl]-1H-indole-5-2H), 2.69-2.64 (m, 4H), 2.46 (s, 3H), 2.32-2.29 carbonylphosphonic acid(m, 1H), 2.18-2.16 (m, 2H), 2.03-2.00 (m, 2H), 1.89-1.85 (m, 3H),1.82-1.63 (m, 3H), 1.62-1.56 (m, 3H), 1.37 (d, J = 6.9 Hz, 3H),0.96-0.92 (m, 15H) 228 I-241 diammonium 2-[[(5S,8S,10aR)- 1257.50 (400MHz, DMSO-d₆) δ 12.06-11.86 (m, 1H), 3-acetyl-8-[[(2S)-4-carbamoyl- 8.99(s, 1H), 8.90-8.80 (m, 1H), 8.51 (d, J = 7.0 1-[2-chloro-3-(3-[[(2S)-1-Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.12-8.02 (m,[(2S,4R)-4-hydroxy-2-[[(1S)-1- 1H), 7.96 (dd, J = 8.7, 1.5 Hz, 1H), 7.89(d, J = [4-(4-methyl-1,3-thiazol-5-yl) 9.1 Hz, 1H), 7.44-7.42 (m, 4H),7.41-7.35 (m, phenyl]ethyl]carbamoyl] 3H), 7.34-7.26 (m, 1H), 7.23-7.17(m, 1H), 7.04- pyrrolidin-1-yl]-3,3-dimethyl-1- 6.99 (m, 1H), 6.91-6.87(m, 1H), 6.81-6.71 (m, oxobutan-2-yl]carbamoyl]propyl) 1H) 5.12-5.04 (m,2H), 4.95-4.88 (m, 1H), 4.54 henoxy]butan-2-yl]carbamoyl]- (d, J = 9.3Hz, 1H), 4.47-4.33 (m, 2H), 4.28-4.25 6-oxo-octahydropyrrolo (m, 2H),4.13-3.81 (m, 4H), 3.70-3.65 (m, 2H), [1,2-a][1,5]diazocin-5-yl]3.62-3.59 (m, 2H), 3.41-3.25 (m, 4H), 2.68-2.61 carbamoyl]-1H-indole-5-(m, 2H), 2.46 (s, 3H), 2.29-2.25 (m, 1H), 2.23- carbonylphosphonate2.10(m, 4H), 2.08-1.97 (m, 2H), 1.88-1.85 (m, 2H), 1.78-1.69 (m, 3H),1.38-1.32 (m, 5H), 1.27- 1.22 (m, 3H), 0.95 (s, 9H) 229 I-243 diammonium2-[[(2S,11S)-2- 1248.45 (300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.03-8.90[(2S)-4-carbamoyl-1-[2-chloro- (m, 3H), 8.41 (d, J = 7.8 Hz, 1H), 8.16(d, J = 7.5 3-(4-[[(2S)-1-[(2S,4R)-4-hydroxy- Hz, 1H), 7.96 (dd, J =8.7, 1.5 Hz, 1H), 7.86 (d, 2-[[(1S)-1-[4-(4-methyl- J = 9.2 Hz, 1H),7.50-7.30 (m, 6H), 7.28 (s, 1H), 1,3-thiazol-5-yl)phenyl]ethyl]7.21-7.17 (m, 1H), 7.12-7.08 (m, 2H), 7.02-6.98carbamoyl]pyrrolidin-1-yl]-3, (m, 2H), 6.92 (dd, J = 7.7, 1.3 Hz, 1H),6.78 (s, 3-dimethyl-1-oxobutan-2-yl] 1H), 5.10 (dd, J = 10.7, 2.9 Hz,1H), 4.98-4.88 carbamoyl]butyl)phenoxy]butan- (m, 1H), 4.76-4.63 (m,1H), 4.53 (d, J = 9.3 Hz, 2-yl]carbamoyl]-12-oxo-1- 1H), 4.45 (t, J =8.0 Hz, 1H), 4.29 (s, 1H), 4.05- azatricyclo[6.4.1.0{circumflex over( )}[4,13]] 3.93 (m, 3H), 3.62-3.61 (m, 2H), 3.55-3.40 (m,trideca-4(13),5,7-trien-11-yl] 3H), 3.31-3.20 (m, 1H), 3.18-3.14 (m,1H), 2.98 carbamoyl]-1H-indole-5- (d, J = 16.5 Hz, 1H), 2.73-2.68 (m,2H), 2.47 (s, carbonylphosphonate 3H), 2.39-2.11 (m, 7H), 2.12-1.97 (m,1H), 1.93- 1.70 (m, 3H), 1.58-1.54 (m, 4H), 1.39 (d, J = 7.0 Hz, 3H),0.95 (s, 9H) 230 I-244 2-[[(2S,11S)-2-[[(2S)-4-carbamoyl- 1280.50 (400MHz, DMSO-d₆) δ 11.88 (s, 1H), 10.27 (br, 1-[5-chloro-2-fluoro-3- 1H),8.99 (s, 1H), 8.98-8.95 (m, 1H), 8.93 (s,(5-[[(2S)-1-[(2S,4R)-4-hydroxy- 1H), 8.52 (d, J = 2.9 Hz, 1H), 8.42 (d,J = 7.8 Hz, 2-[[(1S)-1-[4-(4-methyl-1,3- 1H), 8.15 (d, J = 7.1 Hz, 1H),7.94-7.91 (m, 1H), thiazol-5-yl)phenyl]ethyl] 7.82 (d, J = 9.3 Hz, 1H),7.46-7.36 (m, 6H), 7.27 carbamoyl]pyrrolidin-1-yl]-3,3- (s, 1H),7.14-7.11 (m, 1H), 7.10-7.08 (m, 1H), dimethyl-1-oxobutan-2-yl]7.07-7.05 (m, 1H), 7.00-6.98 (m, 1H), 6.93-6.91carbamoyl]pentyl)phenoxy] (m, 1H), 6.77 (s, 1H), 5.12-5.07 (m, 1H),4.94- butan-2-yl]carbamoyl]-12-oxo-1- 4.90 (m, 1H), 4.73-4.65 (m, 1H),4.52 (d, J = 9.3 azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.30-4.26 (m,4(13),5,7-trien-11-yl]carbamoyl]- 1H), 3.53 (d, J = 4.6 Hz, 3H),2.93-2.83 (m, 1H), 1H-indole-5-carbonylphosphonic 2.46 (s, 3H),2.28-2.22 (m, 3H), 2.16-2.10 (m, acid 3H), 2.04-2.00 (m, 1H), 1.96-1.80(m, 5H), 1.82- 1.78 (m, 2H), 1.70-1.62 (m, 5H), 1.54-1.45 (m, 3H), 1.38(d, J = 7.0 Hz, 3H), 1.28-1.22 (m, 2H), 0.93 (s, 9H) 231 I-2452-[[(2S,11S)-2-[[(1S)-3-carbamoyl- 1158.40 (400 MHz, DMSO-d₆) δ 12.05(s, 1H), 11.10 (s, 1-(diphenylmethylcarbamoyl) 1H), 9.00-8.90 (m, 1H),8.86-8.69 (m, 2H), 8.23 propyl]carbamoyl]-6- (d, J = 7.8 Hz, 1H),7.97-7.94 (m, 1H), 7.54-7.44 [(4-[[1-(2,6-dioxopiperidin-3-yl)- (m, 2H),7.41-7.10 (m, 12H), 7.04-6.96 (m, 2H), 3-methyl-2-oxo-1,3-benzodiazol-6.93-6.69 (m, 4H), 6.07 (d, J = 8.4 Hz, 1H), 5.37-5-yl]methyl]cyclohexyl) 5.32 (m, 1H), 5.12 (d, J = 11.0 Hz, 1H),4.66-4.63 methyl]-12-oxo-1-azatricyclo (m, 1H), 4.32-4.29 (m, 1H),3.32-3.30 (m, 6H), [6.4.1.0{circumflex over ( )}[4,13]]trideca-4(13),3.17-3.11 (m, 2H), 2.94-2.88 (m, 2H), 2.74-2.585,7-trien-11-yl]carbamoyl]-1H- (m, 3H), 2.39-2.36 (m, 1H), 2.29-2.11 (m,3H), indole-5-carbonylphosphonic 2.12-1.97 (m, 3H), 1.91-1.89 (m, 1H),1.78-1.76 acid (m, 2H), 1.66 (d, J = 8.7 Hz, 2H), 1.55-1.36 (m, 5H),0.98-0.85 (m, 2H) 232 I-246 diammonium 2-[[(2S,11S)-2- 1262.50 (400 MHz,DMSO-d₆) δ 11.89 (s, 1H), 9.48 (d, J = [(3-carbamoyl-1-[[2-chloro-3- 4.9Hz, 1H), 8.99 (s, 1H), 8.93 (d, J = 8.6 Hz,(4-[[(2S)-1-[(2S,4R)-4-hydroxy- 1H), 8.50-8.37 (m, 2H), 7.96-7.92 (m,1H), 7.85 2-[[(1S)-1-[4-(4-methyl-1,3- (d, J = 9.3 Hz, 1H), 7.61-7.57(m, 1H), 7.46-7.40 thiazol-5-yl)phenyl]ethyl] (m, 4H), 7.39-7.33 (m,4H), 7.28-7.14 (m, 1H), carbamoyl]pyrrolidin-1-yl]-3,3- 7.16-7.09 (m,3H), 7.03-6.99 (m, 1H), 6.83 (s, dimethyl-1-oxobutan-2-yl] 1H), 5.19 (d,J = 10.5 Hz, 1H), 4.95-4.89 (m, 1H), carbamoyl]butyl)phenyl] 4.69 (s,1H), 4.52 (d, J = 9.0 Hz, 2H), 4.49-4.39 carbamoyl]propyl)carbamoyl]-12-(m, 2H), 4.28 (s, 1H), 3.61 (s, 2H), 3.55-3.41 (m,oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 1H), 3.37 (s, 1H),3.20-3.12 (m, 3H), 3.03 (d, J = trideca-4(13),5,7-trien-11-yl] 16.9 Hz,1H), 2.75-2.62 (m, 3H), 2.46 (s, 3H), carbamoyl]-1H-indole-5- 2.38-2.12(m, 4H), 2.08-1.98 (m, 2H), 1.91-1.89 carbonylphosphonate (m, 1H),1.85-1.74 (m, 1H), 1.59-1.44 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H), 0.94 (s,9H) 233 I-247 diammonium 2-[[(2S,11S)-2- 1249.60 (400 MHz, DMSO-d₆) δ11.93 (s, 1H), 9.50 (s, [[(1S)-3-carbamoyl-1-[[2-chloro- 1H), 9.01-8.89(m, 3H), 8.49 (d, J = 7.2 Hz, 1H), 3-(3-[[(2S)-1-[(2S,4R)-4- 8.41 (d, J= 7.8 Hz, 1H), 7.97-7.91 (m, 2H), 7.58 hydroxy-2-[[(1S)-1-[4-(4-methyl-(d, J = 7.9 Hz, 1H), 7.44-7.38 (m, 7H), 7.35-7.201,3-thiazol-5-yl)phenyl]ethyl] (m, 1H), 7.15-7.06 (m, 3H), 7.01-6.97 (m,1H), carbamoyl]pyrrolidin-1-yl]-3, 6.84 (s, 1H), 5.19 (d, J = 10.6 Hz,1H), 4.95-4.88 3-dimethyl-1-oxobutan-2-yl] (m, 1H), 4.71-4.68 (m, 1H),4.55 (d, J = 9.3 Hz, carbamoyl]propyl)phenyl] 1H), 4.44 (t, J = 7.9 Hz,2H), 4.29 (s, 1H), 3.66- carbamoyl]propyl]carbamoyl]- 3.57 (m, 2H),3.54-3.50 (m, 2H), 3.21-3.17 (m, 12-oxo-1-azatricyclo[6.4.1.0{circumflexover ( )} 1H), 3.14-3.10 (m, 1H), 3.02 (d, J = 16.6 Hz, 1H),[4,13]]trideca-4(13),5,7-trien- 2.71-2.67 (m, 2H), 2.46 (s, 3H),2.38-2.13 (m, 11-yl]carbamoyl]-1H-indole- 7H), 2.06-2.00 (m, 2H),1.92-1.86 (m, 1H), 1.82- 5-carbonylphosphonate 1.74 (m, 4H), 1.38 (d, J= 6.9 Hz, 3H), 0.95 (s, 9H) 234 I-248 diammonium 2-[[(2S,11S)-2- 1213.60(400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 9.96 (s, [(1S)-3-carbamoyl-1-[[3-(3-1H), 9.01-8.90 (m, 3H), 8.39 (dd, J = 17.8, 7.5[[(2S)-1-[(2S,4R)-4-hydroxy-2- Hz, 2H), 7.96-7.84 (m, 2H), 7.47-7.30 (m,9H), [[(1S)-1-[4-(4-methyl-1,3- 7.24-7.05 (m, 6H), 7.01-6.97 (m, 1H),6.91-6.75 thiazol-5-yl)phenyl]ethyl] (m, 2H), 5.18 (dd, J = 10.6, 3.0Hz, 1H), 4.95- carbamoyl]pyrrolidin-1-yl]- 4.89 (m, 1H), 4.73-4.64 (m,1H), 4.57-4.39 (m, 3,3-dimethyl-1-oxobutan-2-yl] 2H), 4.35-4.25 (m, 2H),3.61 (d, J = 3.2 Hz, 2H), carbamoyl]propyl)phenyl]carbamoyl] 3.51-3.47(m, 1H), 3.28-2.95 (m, 4H), 2.46 (s, propyl]carbamoyl]-12-oxo-1- 3H),2.31-1.98 (m, 7H), 1.92-1.70 (m, 6H), 1.38azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] (d, J = 7.0 Hz, 3H),0.94 (s, 9H) trideca-4(13),5,7-trien-11-yl]carbamoyl]-1H-indole-5-carbonyl phosphonate 235 I-2492-[[(2S,11S)-2-[[(1S)-3-carbamoyl- 1275.45 (300 MHz, DMSO-d₆) δ 12.14(s, 1H), 9.49 (s, 1-[[2-chloro-3-(5-[[(2S)- 1H), 9.00-8.97 (m, 2H), 8.83(d, J = 1.6 Hz, 1H), 1-[(2S,4R)-4-hydroxy-2-[[(1S)- 8.47 (d, J = 7.3 Hz,1H), 8.39 (d, J = 7.8 Hz, 1H), 1-[4-(4-methyl-1,3-thiazol- 7.96 (dd, J =8.8, 1.6 Hz, 1H), 7.81 (d, J = 9.3 Hz, 5-yl)phenyl]ethyl]carbamoyl] 1H),7.61-7.52 (m, 2H), 7.50 (d, J = 2.0 Hz, 1H),pyrrolidin-1-yl]-3,3-dimethyl- 7.45-7.40 (m, 4H), 7.34 (s, 1H),7.30-7.20 (m, 1-oxobutan-2-yl]carbamoyl] 1H), 7.17-7.07 (m, 4H),7.05-6.91 (m, 2H), 6.83 pentyl)phenyl]carbamoyl]propyl] (s, 1H), 5.20(dd, J = 10.6, 2.9 Hz, 1H), 4.98-4.88 carbamoyl]-12-oxo-1-azatricyclo(m, 1H), 4.77-4.65 (m, 1H), 4.53 (d, J = 9.2 Hz, [6.4.1.0{circumflexover ( )}[4,13]]trideca- 1H), 4.45-4.40 (m, 2H), 4.29 (s, 1H), 3.62 (s,4(13),5,7-trien-11-yl]carbamoyl]- 2H), 3.58-3.41 (m, 1H), 3.27-3.14 (m,2H), 3.05 1H-indole-5-carbonylphosphonic (dd, J = 17.2, 14.5 Hz, 1H),2.72-2.68 (m, 2H), acid 2.47 (s, 3H), 2.35-2.10 (m, 6H), 2.03-1.96 (m,2H), 1.89-1.74 (m, 2H), 1.60-1.47 (m, 6H), 1.39 (d, J = 7.0 Hz, 3H),1.33-1.24 (m, 1H), 0.94 (s, 9H) 236 I-250 2-[[(2S,11S)-2-[[(1S)-3-1260.65 (300 MHz, DMSO-d₆) δ 12.15 (s, 1H), 9.75 (s,carbamoyl-1-[[2-fluoro-3-(5-[[(2S)- 1H), 9.03-8.96 (m, 2H), 8.84 (s,1H), 8.43-8.39 1-[(2S,4R)-4-hydroxy-2-[[(1S)- (m, 2H), 7.96 (d, J = 8.7Hz, 1H), 7.81 (d, J = 9.3 1-[4-(4-methyl-1,3-thiazol- Hz, 1H), 7.72-7.69(m, 1H), 7.57-7.47 (m, 3H), 5-yl)phenyl]ethyl]carbamoyl] 7.45-7.36 (m,3H), 7.15-7.09 (m, 3H), 7.07-6.98 pyrrolidin-1-yl]-3,3-dimethyl- (m,2H), 6.83 (s, 1H), 5.19 (d, J = 10.6 Hz, 1H), 1-oxobutan-2-yl]carbamoyl]4.96-4.90 (m, 1H), 4.73-4.69 (m, 1H), 4.55-4.40 pentyl)phenyl]carbamoyl](m, 3H), 4.30 (s, 1H), 3.62 (s, 2H), 3.56-3.48 (m,propyl]carbamoyl]-12-oxo-1- 1H), 3.31-3.10 (m, 3H), 3.01 (d, J = 16.7Hz, 1H), azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca-2.62-2.57 (m, 3H), 2.54-2.44 (m, 3H), 2.26-2.214(13),5,7-trien-11-yl]carbamoyl]- (m, 4H), 2.07-1.98(m, 2H), 1.94-1.77(m, 3H), 1H-indole-5-carbonylphosphonic 1.62-1.46 (m, 6H), 1.39 (d, J =7.0 Hz, 3H), 1.33- acid 1.24 (m, 3H), 0.94 (s, 9H) 237 I-251 diammonium2-[[(2S,11S)-2- [(M − (400 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.99 (s,[(2S-4-carbamoyl-1-[2-fluoro- 1)]⁻ = 1H), 8.97-8.90 (m, 2H), 8.41 (d, J= 7.8 Hz, 1H), 3-(5-[[(2S)-1-(2S,4R)-4- 1258.45 8.12 (d, J = 7.6 Hz,1H), 7.98-7.91 (m, 1H), 7.83 hydroxy-2-[[(1S)-1-[4-(4-methyl- (d, J =9.2 Hz, 1H), 7.47-7.35 (m, 5H), 7.26 (s, 1,3-thiazol-5-yl)phenyl]ethyl]2H), 7.13-7.04 (m, 2H), 7.01-6.97 (m, 1H), 6.86carbamoyl]pyrrolidin-1-yl]-3, (s, 2H), 6.76 (s, 1H), 5.13-5.05 (m, 1H),4.93- 3-dimethyl-1-oxobutan-2-yl] 4.89 (m, 1H), 4.71-4.66 (m, 1H), 4.52(d, J = 9.3 carbamoyl]pentyl)-4-methylphenoxy] Hz, 1H), 4.43 (t, J = 8.0Hz, 1H), 4.28 (s, 1H), butan-2-yl]carbamoyl]- 3.96-3.92 (m, 3H), 3.61(s, 2H), 3.48-3.44 (m, 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}1H), 3.22-3.19 (m, 1H), 3.16-3.13 (m, 1H), 2.91-[4,13]]trideca-4(13),5,7- 2.87 (m, 1H), 2.58-2.55 (m, 4H), 2.46 (s, 3H),trien-11-yl]carbamoyl]-1H- 2.32-2.18 (m, 6H), 2.16-2.06 (m, 3H),2.06-1.97 indole-5- (m, 1H), 1.84-1.80 (m, 2H), 1.72-1.68 (m, 1H),carbonylphosphonate 1.57-1.49 (m, 1H), 1.48-1.44 (m, 4H), 1.38 (d, J =7.0 Hz, 3H), 1.36-1.29 (m, 2H), 0.93 (s, 9H) 238 I-252 diammonium2-[[(2S,11S)-2- 1265.00 (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.04-8.88[(2S)-4-carbamoyl-1-[2,4- (m, 3H), 8.41 (d, J = 7.8 Hz, 1H), 8.16 (d, J= 7.4 difluoro-3-(5-[[(2S)-1-[(2S,4R)- Hz, 1H), 7.96 (d, J = 8.7 Hz,1H), 7.82 (d, J = 9.2 4-hydroxy-2-[[(1S)-1-[4-(4- Hz, 1H), 7.51-7.35 (m,7H), 7.28 (s, 1H), 7.13- methyl-1,3-thiazol-5-yl)phenyl] 6.89 (m, 5H),6.77 (s, 1H), 5.09 (dd, J = 10.7, 3.0 ethyl]carbamoyl]pyrrolidin-1- Hz,1H), 4.96-4.88 (m, 1H), 4.73-4.64 (m, 1H),yl]-3,3-dimethyl-1-oxobutan-2- 4.52 (d, J = 9.3 Hz, 1H), 4.43 (t, J =8.0 Hz, 1H), yl]carbamoyl]pentyl)phenoxy] 4.30-4.27 (m, 1H), 4.00-3.92(m, 3H), 3.63-3.60 butan-2-yl]carbamoyl]-12- (m, 2H), 3.54-3.39 (m, 2H),3.28-3.06 (m, 2H), oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,12.90-2.86 (m, 1H), 2.61-2.58 (m, 1H), 2.46 (s,3]]trideca-4(13),5,7-trien-11- 3H), 2.30-2.21 (m, 3H), 2.17-2.00 (m,5H), 1.92- yl]carbamoyl]-1H-indole-5- 1.61 (m, 3H), 1.61-1.42 (m, 5H),1.38 (d, J = 7.0 carbonylphosphonate Hz, 3H), 1.34-1.21 (m, 2H), 0.93(s, 9H) 239 I-253 diammonium 2-[[(2S,11S)-2- 1234.35 (400 MHz, DMSO-d₆)δ 11.90 (s, 1H), 9.05-8.84 [(2S)-4-carbamoyl-1-[2-chloro- (m, 3H), 8.40(d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.6 3-(3-[[(2S)-1-[(2S,4R)-4- Hz, 1H),7.94 (dd, J = 18.9, 9.0 Hz, 2H), 7.49- hydroxy-2-[[(1S)-1-[4-(4-methyl-7.34 (m, 7H), 7.28 (s, 1H), 7.19 (t, J = 7.8 Hz,1,3-thiazol-5-yl)phenyl]ethyl] 1H), 7.09 (t, J = 8.1 Hz, 2H), 7.01-6.97(m, 2H), carbamoyl]pyrrolidin-1-yl]-3, 6.89 (d, J = 7.6 Hz, 1H), 6.77(s, 1H), 5.13-5.06 3-dimethyl-1-oxobutan-2-yl] (m, 1H), 4.97-4.87 (m,1H), 4.68 (t, J = 9.1 Hz, carbamoyl]propyl)phenoxy] 1H), 4.55 (d, J =9.3 Hz, 1H), 4.44 (t, J = 8.0 Hz, butan-2-yl]carbamoyl]-12-oxo- 1H),4.30-4.27 (m, 1H), 4.11-3.87 (m, 4H), 3.65-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 3.61 (m, 2H),3.50-3.43 (m, 1H), 3.26-3.05 (m, trideca-4(13),5,7-trien-11-yl] 2H),2.99-2.94 (m, 1H), 2.71-2.66 (m, 2H), 2.46 carbamoyl]-1H-indole-5- (s,3H), 2.40-2.08 (m, 7H), 2.06-2.01 (m, 1H), carbonylphosphonate 1.95-1.65(m, 5H), 1.38 (d, J = 7.0 Hz, 3H), 0.96 (s, 9H) 240 I-254 diammonium2-[[(2S,11S)-2- [(M − (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.03-8.82[[4-carbamoyl-1-(2-fluoro-3- 1)]⁻ = (m, 3H), 8.43 (d, J = 8.0 Hz, 1H),7.95 (d, J = 8.6 [4-([[(2S)-1-[(2S,4R)-4-hydroxy- 1260.50 Hz, 1H), 7.85(d, J = 8.7 Hz, 1H), 7.51-7.29 (m, 2-[[(1S)-1-[4-(4-methyl-1,3- 7H),7.26-7.20 (m, 1H), 7.16-6.84 (m, 5H), 6.84- thiazol-5-yl)phenyl]ethyl]6.64 (m, 3H), 5.00-4.85 (m, 2H), 4.65 (t, J = 7.8carbamoyl]pyrrolidin-1-yl]-3,3- Hz, 1H), 4.45 (t, J = 7.8 Hz, 1H),4.30-4.27 (m, dimethyl-1-oxobutan-2-yl] 1H), 4.17 (d, J = 9.2 Hz, 1H),4.02-3.92 (m, 3H), carbamoyl]oxy)butyl]phenyl] 3.61-3.58 (m, 2H),3.37-2.98 (m, 6H), 2.74 (s, (methyl)amino)butan-2-yl] 3H), 2.60-2.56 (m,3H), 2.46 (s, 3H), 2.32-2.19 carbamoyl]-12-oxo-1-azatricyclo (m, 2H),2.11-2.02 (m, 4H), 1.81-1.72 (m, 1H), [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13),5,7- 1.68-1.47 (m, 6H), 1.37 (d, J = 7.0 Hz,3H), 0.94 trien-11-yl]carbamoyl]-1H- (s, 9H)indole-5-carbonylphosphonate 241 I-2462-[[(2S,11S)-2-[[(2S)-4-carbamoyl- 1172.45 (300 MHz, DMSO-d₆) δ 12.13(s, 1H), 9.02-9.00 1-[3-([[(2S)-1-[(2S,4R)- (m, 2H), 8.84 (s, 1H), 8.41(d, J = 7.8 Hz, 1H), 4-hydroxy-2-[[(1S)-1-[4-(4- 8.17 (d, J = 8.1 Hz,1H), 8.06 (d, J = 9.3 Hz, 1H), methyl-1,3-thiazol-5-yl)phenyl] 7.96 (dd,J = 8.7, 1.6 Hz, 1H), 7.60-7.36 (m, 6H), ethyl]carbamoyl]pyrrolidin-1-7.27 (s, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.13-7.11yl]-3,3-dimethyl-1-oxobutan- (m, 2H), 7.05-6.96 (m, 1H), 6.88-6.86 (m,2H), 2-yl]carbamoyl]methyl)phenoxy] 6.82-6.74 (m, 2H), 5.13-5.09 (m,2H), 4.98-4.89 butan-2-yl]carbamoyl]-12- (m, 1H), 4.74-4.67 (m, 1H),4.58-4.40 (m, 2H), oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} (m,1H), 4.05-3.98 (m, 1H), 3.92-3.89 [4,13]]trideca-4(13),5,7-trien-11- (m,2H), 3.65-3.60 (m, 3H), 3.55-3.36 (m, 2H), yl]carbamoyl]-1H-indole-5-3.25-3.10 (m, 2H), 2.90-2.86 (m, 1H), 2.47 (s, carbonylphosphonic acid3H), 2.31-2.12 (m, 6H), 2.10-1.96 (m, 1H), 1.94- 1.62 (m, 3H), 1.38 (d,J = 7.0 Hz, 3H), 0.93 (s, 9H) 242 I-2572-[[(2S,11S)-2-[[(1S)-3-carbamoyl- [(M − (400 MHz, DMSO-d₆) δ 12.09 (s,1H), 10.15 (s, 1-[[3-chloro-5-(5[[(2S)- 1)]⁻ = 1H), 8.99-8.95 (m, 2H),8.84 (s, 1H), 8.45 (d, J = 1-[(2S,4R)-4-hydroxy-2-[[(1S)- 1274.40 7.2Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.96 (d, J =1-[4-(4-methyl-1,3-thiazol- 8.8 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.63(s, 5-yl)phenyl]ethyl]carbamoyl] 1H), 7.56-7.46 (m, 2H), 7.45-7.43 (m,2H), 7.39- pyrrolidin-1-yl]-3,3-dimethyl- 7.37 (m, 2H), 7.35-7.33 (m,1H), 7.25 (s, 1H), 1-oxobutan-2-yl]carbamoyl] 7.14 (d, J = 7.3 Hz, 1H),7.09 (d, J = 7.7 Hz, 1H), pentyl)phenyl]carbamoyl]propyl] 7.02-6.92 (m,2H), 6.81 (s, 1H), 5.19-5.11 (m, carbamoyl]-12-oxo-1-azatricyclo 2H),4.96-4.88 (m, 1H), 4.73-4.65 (m, 1H), 4.52 [6.4.1.0{circumflex over( )}[4,13]]trideca- (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.30-4(13),5,7-trien-11-yl]carbamoyl]- 4.26 (m, 3H), 3.64-3.60 (m, 2H),3.54-3.44 (m, 1H-indole-5-carbonylphosphonic 1H), 3.39-3.32 (m, 1H),3.28-3.06 (m, 3H), 3.03- acid 2.98 (m, 1H), 2.46 (s, 3H), 2.37-1.72 (m,10H), 1.62-1.43 (m, 5H), 1.38 (d, J = 6.9 Hz, 3H), 1.28- 1.22 (m, 2H),0.93 (s, 9H) 243 I-258 2-[[(2S,11S)-2-[[(1S)-3- 1255.55 (400 MHz,DMSO-d₆) δ 12.11 (s, 1H), 9.85 (s, carbamoyl-1-[[3-(5-[[(2S)-1-[(2S,1H), 9.03-8.92 (m, 2H), 8.83 (s, 1H), 8.38-3.354R)-4-hydroxy-2-[[(1S)-1-[4-(4- (m, 2H), 7.96 (dd, J = 8.8, 1.6 Hz, 1H),7.79 (d, methyl-1,3-thiazol-5-yl)phenyl] J = 9.2 Hz, 1H), 7.54 (d, J =8.7 Hz, 1H), 7.48 (s, ethyl]carbamoyl]pyrrolidin- 1H), 7.44 (d, J = 8.2Hz, 2H), 7.38 (d, J = 8.2 Hz, 1-yl]-3,3-dimethyl-1-oxobutan- 2H), 7.32(s, 1H), 7.24 (s, 1H), 7.18 (s, 1H), 7.14 2-yl]carbamoyl]pentyl)-5- (d,J = 7.3 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.01- methylphenyl]carbamoyl]6.97 (m, 1H), 6.79 (s, 1H), 6.69 (s, 1H), 5.20-5.11propyl]carbamoyl]-12-oxo-1- (m, 2H), 4.96-4.88 (m, 1H), 4.72-4.67 (m,1H), azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]trideca- 4.52 (d, J= 9.3 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H),4(13),5,7-trien-11-yl]carbamoyl]- 4.32-4.27 (m, 2H), 3.64-3.59 (m, 2H),3.53-3.43 1H-indole-5-carbonylphosphonic (m, 1H), 3.29-3.05 (m, 3H),3.05-2.95 (m, 1H), acid 2.47-2.44 (m, 5H), 2.30-2.20 (m, 6H), 2.19-2.08(m, 3H), 2.06-1.72 (m, 4H), 1.61-1.42 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H),1.29-1.22 (m, 2H), 0.93 (s, 9H) 244 I-259 6342-[[(2S,11S)-2-[[(1S)-3-1256.45 (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 9.39 (s,carbamoyl-1-[[3-(5-[[(2S)-1-[(2S, 1H), 9.06-8.92 (m, 2H), 8.84 (s, 1H),8.37 (t, J = 4R)-4-hydroxy-2-[[(1S)-1- 7.3 Hz, 2H), 7.97 (d, J = 8.8 Hz,1H), 7.81 (d, J = [4-(4-methyl-1,3-thiazol-5-yl) 9.3 Hz, 1H), 7.56-7.35(m, 7H), 7.19-6.93 (m, phenyl]ethyl]carbamoyl] 6H), 6.81 (s, 1H), 5.20(d, J = 10.5 Hz, 1H), 4.98- pyrrolidin-1-yl]-3,3-dimethyl-1- 4.89 (m,1H), 4.74-4.67 (m, 1H), 4.54 (d, J = 9.3oxobutan-2-yl]carbamoyl]pentyl)- Hz, 1H), 4.47-4.39 (m, 2H), 4.32-4.28(m, 1H), 2-methylphenyl]carbamoyl] 3.64-3.61 (m, 2H), 3.58-3.00 (m, 7H),2.59-2.56 propyl]carbamoyl]-12-oxo-1- (m, 2H), 2.47 (s, 3H), 2.37-2.09(m, 6H), 2.06 (s, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 3H),2.03-1.72 (m, 2H), 1.60-1.45 (m, 6H), 1.39trideca-4(13),5,7-trien-11-yl] (d, J = 7.0 Hz, 3H), 1.35-1.18 (m, 2H),0.95 (s, carbamoyl]-1H-indole-5- carbonylphosphonic acid 9H) 245 I-260diammonium 2-[[(2S,11S)-2- 1186.50 (300 MHz, DMSO-d₆) δ 11.92 (s, 1H),9.00-8.92 [[(2S)-4-carbamoyl-1-[3-(2- (m, 2H), 8.43 (d, J = 7.7 Hz, 1H),8.13 (d, J = 8.0 [[(2S)-1-[(2S,4R)-4-hydroxy-2- Hz, 1H), 8.02-7.84 (m,2H), 7.50-7.35 (m, 6H), [[(1S)-1-[4-(4-methyl-1,3-thiazol- 7.29 (s, 1H),7.22-7.05 (m, 3H), 7.03-6.98 (m, 5-yl)phenyl]ethyl]carbamoyl] 1H),6.88-6.67 (m, 5H), 5.11 (d, J = 10.7 Hz, 1H),pyrrolidin-1-yl]-3,3-dimethyl- 4.98-4.89 (m, 1H), 4.73-4.66 (m, 1H),4.55 (d, J = 1-oxobutan-2-yl]carbamoyl] 9.3 Hz, 1H), 4.45 (t, J = 8.0Hz, 1H), 4.32-4.28 ethyl)phenoxy]butan-2-yl] (m, 1H), 4.00-3.89 (m, 3H),3.65-3.60 (m, 2H), carbamoyl]-12-oxo-1-azatricyclo 3.55-3.34 (m, 1H),3.24-3.08 (m, 3H), 2.98-2.70 [6.4.1.0{circumflex over( )}[4,13]]trideca-4 (m, 3H), 2.65-2.58 (m, 1H), 2.47 (s, 3H), 2.44-(13),5,7-trien-11-yl]carbamoyl]- 2.37 (m, 1H), 2.34-1.98 (m, 6H),1.88-1.68 (m, 1H-indole-5-carbonylphosphonate 4H), 1.39 (d, J = 7.0 Hz,3H), 0.92 (s, 9H) 246 I-261 2-[[(2S,11S)-2-[[(2S)-4-carbamoyl- 1218.40(300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 9.02-8.99 1-[2-fluoro-3-(3-[[(2S)-(m, 2H), 8.84 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H),1-[(2S,4R)-4-hydroxy-2-[[(1S)- 8.22-8.10 (m, 1H), 7.93 (dd, J = 20.5,9.0 Hz, 1-[4-(4-methyl-1,3-thiazol-5- 2H), 7.58-7.35 (m, 6H), 7.32-7.27(m, 1H), 7.16- yl)phenyl]ethyl]carbamoyl] 6.94 (m, 5H), 6.90-6.70 (m,2H), 5.10 (dd, J = pyrrolidin-1-yl]-3,3-dimethyl-1- 11.1 2.8 Hz, 1H),4.98-4.91 (m, 1H), 4.73-4.67 oxobutan-2-yl]carbamoyl] (m, 1,H), 4.55 (d,J = 9.2 Hz, 1H), 4.44 (t, J = 8.0 propyl)phenoxy]butan-2-yl] Hz, 1H),4.32-4.28 (m, 1H), 4.05-3.95 (m, 3H), carbamoyl]-12-oxo-1-azatricyclo3.66-3.61 (m, 2H), 3.57-3.01 (m, 7H), 2.92-2.87 [6.4.1.0{circumflex over( )}[4,13]]trideca-4(13),5, (m, 1H), 2.62-2.57 (m, 2H), 2.47 (s, 3H),2.37- 7-trien-11-yl]carbamoyl]-1H- 2.00 (m, 6H), 1.94-1.61 (m, 5H), 1.39(d, J = 7.0 indole-5-carbonylphosphonic Hz, 3H), 0.96 (s, 9H) acid 247I-262 2-[[(5S,8S,10aR)-3-acetyl-8- 1284.55 (400 MHz, DMSO-d₆) δ 8.99 (s,1H), 8.92-8.80 [[(2S)-4-carbamoyl-1-[2-fluoro- (m, 1H), 8.52-8.40 (m,2H), 8.11-8.04 (m, 1H), 3-(5-[[(2S)-1-[(2S,4R)-4- 7.97 (dd, J = 8.7, 1.6Hz, 1H), 7.81 (d, J = 9.3 Hz, hydroxy-2-[[(1S)-1-[4-(4-methyl- 1H),7.49-7.34 (m, 7H), 7.34-7.23 (m, 1H), 6.84-1,3-thiazol-5-yl)phenyl]ethyl] 6.80 (m, 2H), 6.62-6.60 (m, 1H),5.05-5.01 (m, carbamoyl]pyrrolidin-1-yl]-3, 1H), 4.96-4.89 (m, 1H), 4.52(d, J = 9.4 Hz, 1H), 3-dimethyl-1-oxobutan-2-yl] 4.48-4.34 (m, 2H),4.29-4.23 (m, 2H), 4.10-3.80 carbamoyl]pentyl)-5-methylphenoxy] (m, 4H),3.75-3.70 (m, 2H), 3.65-3.60 (m, 2H), butan-2-yl]carbamoyl]- 3.43-3.32(m, 2H), 2.46 (s, 3H), 2.33-2.17 (m, 6-oxo-octahydropyrrolo[1,2- 8H),2.17-1.98 (m, 6H), 1.96-1.62 (m, 8H), 1.62-a][1,5]diazocin-5-yl]carbamoyl]- 1.43 (m, 6H), 1.38 (d, J = 7.0 Hz, 3H),1.32-1.20 1H-indole-5- (m, 2H), 0.93 (s, 9H) carbonylphosphonic acid 248I-263 2-[[(5S,8S,10aR)-3-acetyl-8- 1255.45 (300 MHz, DMSO-d₆) δ12.21-12.01 (m, 1H), [[(2S)-4-carbamoyl-1-[2-fluoro- 9.05-8.98 (m, 1H),8.87-8.78 (m, 1H), 8.52 (d, J = 3-(4-[[(2S)-1-[(2S,4R)-4- 6.9 Hz, 1H),8.39 (d, J = 7.7 Hz, 1H), 8.09 (d, hydroxy-2-[[(1S)-1-[4-(4-methyl- J =8.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.84 (d,1,3-thiazol-5-yl)phenyl]ethyl] J = 9.2 Hz, 1H), 7.53-7.36 (m, 6H),7.30-7.25 (m, carbamoyl]pyrrolidin-1-yl]-3, 1H), 7.06-6.98 (m, 2H),6.85-6.80 (m, 2H), 5.08- 3-dimethyl-1-oxobutan-2-yl] 5.04 (m 2H),4.96-4.89 (m, 1H), 4.58-4.52 (m, carbamoyl]butyl)phenoxy] 1H),4.4,2-4.38 (m, 2H), 4.31-4.26 (m, 2H), 4.05-butan-2-yl]carbamoyl]-6-oxo- 4.01 (m, 3H), 3.94-3.90 (m, 1H), 3.73-3.69(m, octahydropyrrolo[1,2-a][1,5] 3H), 3.64-3.58 (m, 4H), 3.49-3.45 (m,3H), 2.62- diazocin-5-yl]carbamoyl]-1H- 2.58 (m, 2H), 2.47 (s, 3H),2.35-2.28 (m, 1H), indole-5-carbonylphosphonic 2.24-2.16 (m, 6H),2.04-1.99 (m, 2H), 1.87-1.68 acid (m, 5H), 1.54-1.50 (m, 4H), 1.39 (d, J= 6.9 Hz, 3H), 0.95 (s, 9H) 249 I-264 63 2-[[(2S,11S)-2-[[(1S)-3-1259.55 (400 MHz, DMSO-d₆) δ 12.12-12.08 (m, 1H),carbamoyl-1-[[3-fluoro-5-(5-[[(2S)- 10.19-10.12 (m, 1H), 9.06-8.92 (m,2H), 8.83 (d, 1-[(2S,4R)-4-hydroxy-2- J = 1.6 Hz, 1H), 8.45-8.38 (m,2H), 7.96 (d, J = [[(1S)-1-[4-(4-methyl-1,3-thiazol- 8.8 Hz, 1H), 7.80(d, J = 9.2 Hz, 1H), 7.53 (d, J = 5-yl)phenyl]ethyl]carbamoyl] 8.8 Hz,1H), 7.48 (d, J = 2.1 Hz, 1H), 7.46-7.30 pyrrolidin-1-yl]-3,3-dimethyl-(m, 6H), 7.18-7.05 (m, 3H), 7.01-6.96 (m, 1H),1-1-oxobutan-2-yl]carbamoyl] 6.86-6.76 (m, 1H), 6.76-6.68 (m, 1H),5.19-5.12 pentyl)phenyl]carbamoyl]propyl] (m, 2H), 4.96-4.88 (m, 1H),4.74-4.64 (m, 1H), carbamoyl]-12-oxo-1- 4.51 (d, J = 9.3 Hz, 1H),4.46-4.39 (m, 1H), 4.30- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 4.25 (m, 2H), 3.65-3.58 (m, 2H), 3.56-3.42 (m,4(13),5,7-trien-11-yl]carbamoyl]- 2H), 3.26-3.17 (m, 1H), 3.15-3.09 (m,1H), 3.04- 1H-indole-5- 2.98 (m), 2.46 (s, 3H), 2.30-2.19 (m, 4H), 2.18-carbonylphosphonic acid 7 2.08 (m, 3H), 2.05-1.73 (m, 4H), 1.58-1.46 (m,6H), 1.38 (d, J = 7.0 Hz, 3H), 1.29-1.20 (m, 2H), 0.93 (s, 9H) 250 I-265diammonium 2-[[(2S,11S)-2- 1246.55 (400 MHz, DMSO-d₆) δ 12.01-11.85 (m,1H), [(4-carbamoyl-1-[[2-fluoro-3- 9.08-8.89 (m, 3H), 8.39 (d, J = 8.9Hz, 1H), 8.09- (5-[[(2S)-1-[(2S,4R)-4-hydroxy- 8.03 (m, 1H), 7.98-7.91(m, 1H), 7.83-7.78 (m, 2-[[(1S)-1-[4-(4-methyl-1,3- 1H), 7.47-7.38 (m,6H), 7.36-7.30 (m, 2H), 7.17- thiazol-5-yl)phenyl]ethyl] 7.07 (m, 2H),7.05-6.95 (m, 1H), 6.81 (d, J = 8.1 carbamoyl]pyrrolidin-1-yl]-3,3- Hz,1H), 6.79-6.73 (m, 1H), 6.67-6.60 (m, 1H), dimethyl-1-oxobutan-2-yl]6.42-6.36 (m, 1H), 5.36-5.22 (m, 1H), 5.14-5.02carbamoyl]pentyl)phenyl]amino] (m, 1H), 4.96-4.88 (m, 1H), 4.72-4.68 (m,1H), butan-2-yl)carbamoyl]-12-oxo- 4.54-4.41 (m, 2H), 4.30-4.25 (m, 1H),3.87-3.81 1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] (m, 1H),3.64-3.59 (m, 2H), 3.51-3.20 (m, 3H), trideca-4(13),5,7-trien-11-yl]3.19-3.07 (m, 5H), 2.92-2.88 (m, 1H), 2.76-2.72 carbamoyl]-1H-indole-5-(m, 1H), 2.45 (s, 3H), 2.13-2.06 (m, 3H), 2.04- carbonylphosphonate 2.00(m, 4H), 1.80-1.76 (m, 2H), 1.52-1.47 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H),1.26-1.22 (m, 2H), 0.93 (s, 9H) 251 I-2662-[[(2S,11S)-2-[[(2S)-4-carbamoyl- 1260.55 (400 MHz, DMSO-d₆) δ11.95-11.88 (m, 1H), 1-[2-fluoro-3-(5-[[(2S)- 9.02-8.89 (m, 3H), 8.40(d, J = 7.7 Hz, 1H), 8.18- 1-[(2S,4R)-4-hydroxy-2-[[(1S)- 8.11 (m, 1H),7.95 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 1-[4-(4-methyl-1,3-thiazol-5- 9.2Hz, 1H), 7.52-7.33 (m, 6H), 7.28-7.24 (m, yl)phenyl]ethyl]carbamoyl]1H), 7.12-7.05 (m, 2H), 7.01-6.95 (m, 1H), 6.87-pyrrolidin-1-yl]-3,3-dimethyl-1- 6.72 (m, 2H), 6.66-6.55 (m, 1H), 5.09(dd, J = oxobutan-2-yl]carbamoyl] 10.7, 2.8 Hz, 1H), 4.95-4.89 (m, 1H),4.72-4.65 pentyl)-5-methylphenoxy]butan- (m, 1H), 4.55-4.49 (m, 1H),4.46-4.39 (m, 1H), 2-yl]carbamoyl]-12-oxo-1- 4.31-4.24 (m, 1H),3.98-3.85 (m, 3H), 3.66-3.58 azatricyclo[6.4.1.[4,13]]trideca- (m, 2H),3.49-3.41 (m, 3H), 3.30-3.26 (m, 3H), 4(13),5,7-trien-11-yl]carbamoyl]-2.91-2.85 (m, 1H), 2.46 (s, 3H), 2.32-2.22 (m,1H-indole-5-carbonylphosphonic 7H), 2.17-1.98 (m, 4H), 1.90-1.64 (m,4H),1.61- acid 1.42 (m, 4H), 1.38 (d, J = 6.9 Hz, 3H), 1.29-1.22 (m, 2H),0.93 (s, 9H) 252 I-267 (diammonium 2-[[(2S,11S)-2- 1264.50 400 MHz,DMSO-d₆) δ 11.92-11.85 (m, 1H), [[(2S)-4-carbamoyl-1-[2,5- 8.99-8.89 (m,3H), 8.40 (d, J = 7.8 Hz, 1H), 8.15 difluoro-3-(5-[[(2S)-1-[(2S,4R)-4-(d, J = 7.2 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.81hydroxy-2-[[(1S)-1-[4-(4-methyl- (d, J = 9.2 Hz, 1H), 7.47-7.31 (m, 6H),7.28-7.21 1,3-thiazol-5-yl)phenyl] (m, 1H), 7.13-7.03 (m, 2H), 7.01-6.93(m, 2H), ethyl]carbamoyl]pyrrolidin-1- 6.81-6.64 (m, 2H), 5.09 (dd, J =10.8, 2.9 Hz, yl]-3,3-dimethyl-1-oxobutan-2- 1H), 4.98-4.86 (m, 1H),4.74-4.65 (m, 1H), 4.57- yl]carbamoyl]pentyl)phenoxy] 4.51 (m, 1H),4.46-4.38 (m, 1H), 4.32-4.25 (m, butan-2-yl]carbamoyl]-12- 1H),4.06-3.91 (m, 4H), 3.64-3.56 (m, 2H), 3.51-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]] 3.38 (m, 1H),3.25-3.07 (m, 2H), 2.91-2.85 (m, trideca-4(13),5,7-trien-11- 1H),2.63-2.52 (m, 3H), 2.46 (s, 3H), 2.33-2.10 yl]carbamoyl]-1H-indole-5-(m, 4H), 2.19-2.09 (m, 3H), 2.08-1.98 (m, 1H), carbonylphosphonate1.85-1.75 (m, 1H), 1.73-1.63 (m, 1H), 1.62-1.64 (m, 5H), 1.38 (d, J =7.0 Hz, 3H), 1.33-1.21 (m, 2H), 0.93 (s, 9H) 253 I-2682-[[(2S,11S)-2-[[(1S)-3- 1199.50 (300 MHz, DMSO-d₆) δ 11.97-11.91 (m,1H), carbamoyl-1-[4-(5-[[(2S)-1-[(2S,4R)- 9.68-9.62 (m, 1H), 9.04-8.89(m, 3H), 8.69 (d, J = 4-hydroxy-2-[[(1S)-1-[4- 7.7 Hz, 1H), 8.45-8.34(m, 2H), 7.95 (d, J = 8.6 (4-methyl-1,3-thiazol-5-yl) Hz, 1H), 7.84 (d,J = 9.1 Hz, 1H), 7.51-7.38 (m, phenyl]ethyl]carbamoyl]pyrrolidin- 6H),7.31-7.25 (m, 1H), 7.19-7.03 (m, 3H), 7.01-1-yl]-3,3-dimethyl-1-oxobutan- 6.92 (m, 1H), 6.82-6.75 (m, 1H), 5.11(dd, J = 2-yl]carbamoyl]pentyl) 10.8, 2.9 Hz, 1H), 4.99-4.87 (m, 1H),4.72-4.66 pyridin-2-yl]propyl]carbamoyl]- (m, 2H), 4.58-4.39 (m, 2H),4.33-4.26 (m, 1H), 12-oxo-1-azatricyclo [6.4.1.0{circumflex over ( )}3.75-3.45 (m, 4H), 2.87-2.61 (m, 5H), 2.47 (s,[4,13]]trideca-4(13),5,7-trien- 3H), 2.31-2.19 (m, 1H), 2.14-2.01 (m,4H), 1.99- 11-yl]carbamoyl]-1H-indole- 1.75 (m, 4H), 1.72-1.59 (m, 5H),1.58-1.52 (m, 5-carbonylphosphonic acid 2H), 1.39 (d, J = 6.9 Hz, 3H),1.35-1.21 (m, 2H), 0.95 (s, 9H) 254 I-269 2-[[(2S,11S)-2-[[(1S)-3-1148.40 (400 MHz, DMSO-d₆) δ 12.11-12.05 (m, 1H), Carbamoyl-1-11.12-11.06 (m, 1H), 8.93 (d, J = 7.6 Hz, 1H), (diphenylmethylcarbamoyl)8.81 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.32 (d, J =propyl]carbamoyl]-7- 7.7 Hz, 1H), 8.02-7.91 (m, 1H), 7.49 (d, J = 8.8([6-[1-(2,6-dioxopiperidin-3-yl)- Hz, 1H), 7.35-7.22 (m, 12H), 7.08-6.96(m, 3H), 3-methyl-2-oxo-1,3-benzodiazol- 6.86 (d, J = 8.1 Hz, 1H),6.76-6.71 (m, 1H), 6.64 5-yl]hexyl]oxy)-12-oxo- (d, J = 8.3 Hz, 1H),6.08 (d, J = 8.4 Hz, 1H), 5.38- 1-azatricyclo[6.4.1.0{circumflex over( )}[4,13]] 5.32 (m, 1H), 5.08 (dd, J = 11.1, 4.9 Hz 1H)trideca-4(13),5,7-trien-11-yl] 4.77-4.65 (m,1H), 4.33-4.28 (m, 1),4.03-3.94 carbamoyl]-1H-indole-5- (m, 2H), 3.54-3.39 (m, 2H), 3.31 (s,3H), 3.17- carbonylphosphonic acid 3.08 (m, 2H), 2.97-2.76 (m, 3H),2.76-2.67 (m, 1H), 2.66-2.56 (m, 3H), 2.24-2.09 (m, 4H), 2.04- 1.96 (m,1H), 1.95-1.83 (m, 1H), 1.83-1.74 (m, 3H), 1.68-1.60 (m, 2H), 1.53-1.46(m, 2H), 1.42- 1.26 (m, 2H) 255 I-270 2-[[(2S,11S)-2-[[(1S)-3-carbamoyl-1120.40 (300 MHz, DMSO-d₆) δ 12.15-12.06 (m, 1H),1-(diphenylmethylcarbamoyl) 11.12-11.06 (m, 1H), 8.95 (d, J = 7.7 Hz,1H), propyl]carbamoyl]-7-[4- 8.85-8.76 (m, 2H), 8.37-8.17 (m, 1H), 7.97(d, J = [1-(2,6-dioxopiperidin-3-yl)- 8.6 Hz, 1H), 7.61-7.43 (m, 2H),7.41-7.19 (m, 3-methyl-2-oxo-1,3-benzodiazol- 11H), 7.11-6.98 (m, 3H),6.93 (d, J = 7.3 Hz, 1H), 5-yl]butoxy]-12-oxo-1- 6.83-6.62 (m, 2H), 6.09(d, J = 8.2 Hz, 1H), 5.44- azatricyclo[6.4.1.0{circumflex over( )}[4,13]]trideca- 5.28 (m, 1H), 5.08 (dd, J = 11.1, 4.9 Hz, 1H),4(13),5,7-trien-11-yl]carbamoyl]- 4.79-4.58 (m, 1H), 4.41-4.26 (m, 1H),4.10-3.97 1H-indole-5- (m, 3H), 3.34 (s, 3H), 3.23-3.05 (m, 1H), 3.06-carbonylphosphonic acid 2.95 (m, 2H), 2.93-2.79 (m, 2H), 2.79-2.58 (m,4H), 2.32-1.94 (m, 6H), 1.92-1.67 (m, 6H) 256 I-2712-[[(5S,8S,10aR)-8-[[(1S)-3- 1181.60 (300 MHz, DMSO-d₆) δ 12.17-11.98(m, 1H), carbamoyl-1- 11.12-11.06 (m, 1H), 8.85-8.71 (m, 2H), 8.46 (d,(diphenylmethylcarbamoyl) J = 6.8 Hz, 1H), 8.26-8.21 (m, 1H), 8.04-7.96(m, propyl]carbamoyl]- 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.50-7.41 (m, 1H),6-oxo-3-[4-[(1r,4s)-4-[1-(2,6- 7.39-7.20 (m, 11H), 7.10-6.96 (m, 2H),6.95-6.86 dioxopiperidin-3-yl)-3-methyl- (m, 1H), 6.81-6.75 (m, 1H),6.11 (dd, J = 8.5, 3.3 2-oxo-1,3-benzodiazol-5-yl] Hz, 1H), 5.34 (dd, J= 13.1, 5.0 Hz, 1H), 5.05- cyclohexyl]butanoyl]- 4.92 (m, 1H), 4.55-4.14(m, 3H), 3.89 (m, 2H), octahydropyrrolo[1,2-al [1,5]diazocin-3.58-3.42(m, 3H), 3.34 (s, 3H), 2.96-2.89 (m,5-yl]carbamoyl]-1H-indole-5- 2H), 2.76-2.55 (m, 6H), 2.25-1.82 (m, 5H),1.82- carbonylphosphonic acid 1.41 (m, 18H) 257 I-272 diammonium2-[[(2S,11S)-2- 1288.55 (400 MHz, DMSO-d₆) δ 11.96-11.92 (m, 1H),[[(2S)-143-(5-[[(2S)-1-[(2S,4R)- 8.97 (d, J = 17.8 Hz, 2H), 8.94-8.88(m, 1H), 8.44 4-(acetyloxy)-2-[[(1S)-1-[4- (d, J = 7.7 Hz, 1H), 8.16 (d,J = 7.4 Hz, 1H), 7.96 (4-methyl-1,3-thiazol-5-yl) (d, J = 8.7 Hz, 1H),7.84 (d, J = 8.7 Hz, 1H), 7.47- phenyl]ethyl]carbamoyl]pyrrolidin- 7.41(m, 4H), 7.38 (d, J = 8.2 Hz, 2H), 7.32-7.26 1-yl]-3,3-dimethyl-1-oxo(m, 1H), 7.13-7.04 (m, 2H), 7.03-6.92 (m, 3H),butan-2-yl]carbamoyl]pentyl)- 6.87-6.81 (m, 1H), 6.79-6.72(m, 1H),5.23-5.17 2-fluorophenoxy]-4-carbamoylbutan- (m, 1H), 5.09 (dd, J =10.7, 3.0 Hz, 1H), 4.95- 2-yl]carbamoyl]-12- 4.89 (m, 1H), 4.72-4.64 (m1H), 4.50-4.43 (m, oxo-1-azatricyclo [6.4.1.0{circumflex over( )}[4,13]] 1H), 4.36 (d, J = 8.7 Hz, 1H), 4.03-3.91 (m, 4H),trideca-4(13),5,7-trien-11- 3.78-3.71 (m, 1H), 3.52-3.40 (m, 2H),3.28-3.15 yl]carbamoyl]-1H-indole-5- (m, 1H), 3.16-3.08 (m, 1H),2.92-2.85 (m, 1H), carbonylphosphonate 2.62-2.55 (m, 2H), 2.46 (s, 3H),2.30-2.18 (m, 5H), 2.19-2.06 (m, 3H), 2.00 (s, 3H), 1.87-1.81 (m, 1H),1.74-1.67 (m, 1H), 1.62-1.44 (m, 5H), 1.38 (d, J = 7.0 Hz, 3H),1.32-1.24 (m, 2H), 0.95 (s, 9H) 258 I-273 2-[[(5S,8S,10aR)-8-[[(1S)-3-1167.55 (400 MHz, DMSO-d₆) δ 12.18-12.13 (m, 1H), carbamoyl-1-11.12-11.06 (m, 1H), 8.86-8.72 (m, 2H), 8.54- (diphenylmethylcarbamoyl)8.45 (m, 1H), 8.24-8.18 (m, 1H), 7.96 (d, J = 8.8 propyl]carbamoyl]- Hz,1H), 7.57-7.40 (m, 2H), 7.38-7.18 (m, 11H),6-oxo-3-[3-[(1s,4s)-4-[1-(2,6- 7.09-6.95 (m, 2H), 6.88 (d, J = 7.4 Hz,1H), 6.78- dioxopiperidin-3-yl)-3-methyl- 6.69 (m, 1H), 6.11 (dd, J =8.5, 3.3 Hz, 1H), 5.37- 2-oxo-1,3-benzodiazol-5-yl] 5.29 (m, 1H), 5.08(dd, J = 11.1, 4.9 Hz, 1H), cyclohexyl]propanoyl]- 4.49-4.42 (m, 1H),4.43-4.36 (m, 2H), 4.22-4.20 octahydropyrrolo[1,2-a][1,5] (m, 1H),3.96-3.89 (m, 1H), 3.77-3.65 (m, 2H), diazocin-5-yl]carbamoyl]-1H- 3.34(s, 3H), 2.96-2.81 (m, 1H), 2.77-2.57 (m, indole-5- 3H), 2.20-2.06 (m,4H), 2.05-1.96 (m, 4H), 1.95- carbonylphosphonic acid 1.85 (m, 6H),1.85-1.62 (m, 2H), 1.51-1.48 (m, 6H), 1.29-1.25 (m, 2H), 1.09-1.07 (m,2H) 259 I-274 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1181.55 (400 MHz, CD₃OD) δ8.88-8.85 (m, 1H), 8.08- carbamoyl-1- 8.04 (m, 1H), 7.55-7.53 (m, 1H),7.44-7.18 (m, (diphenylmethylcarbamoyl) 11H), 7.06-6.95 (m, 2H),6.89-6.80 (m, 1H), propyl]carbamoyl]- 6.20-6.14 (m, 1H), 5.34-5.24 (m,1H), 5.15-5.09 6-oxo-3-[4-[(1s,4r)-4-[1-(2,6- (m, 1H), 4.53-4.50 (m,2H), 4.36-7.34 (m, 1H), dioxopiperidin-3-yl)-3-methyl- 4.05-3.6 (m, 1H),3.85-3.83 (m, 2H), 3.56-3.54 2-oxo-1,3-benzodiazol-5-yl] (m, 1H), 3.40(s, 3H), 3.01-2.88 (m, 1H), 2.86- cyclohexyl]butanoyl]- 2.76 (m, 2H),2.67-2.60 (m, 2H), 2.52-2.50 (m, octahydropyrrolo[1,2-a][1,5] 1H),2.42-2.39 (m, 2H), 2.29-2.13 (m, 4H), 2.05-diazocin-5-yl]carbamoyl]-1H-indole-5- 1.66 (m, 11H), 1.56-1.44 (m, 2H),1.38-1.33 (m, carbonylphosphonic acid 3H), 1.15-1.32 (m, 2H) 260 I-275diammonium 2-[[5S,8S,10aR)- 1270.55 (400 MHz, DMSO-d₆) δ 12.09-11.79 (m,1H), 3-acetyl-8-[[(2S)-4-carbamoyl- 8.99 (s, 1H), 8.92-8.78 (m, 1H),8.52-8.38 (m, 1-[2-fluoro-3-(5-[[(2S)-1- 1H), 8.12-8.02 (m, 1H),7.99-7.93 (m, 1H), 7.80 [(2S,4R)-4-hydroxy-2-[[(1S)-1- (d, J = 9.1 Hz,1H), 7.46-7.33 (m, 7H), 7.31-7.24 [4-(4-methyl-1,3-thiazo1-5-yl) (m,1H), 7.02-6.97 (m, 2H), 6.84-6.79 (m, 2H), phenyl]ethyl]carbamoyl] (m,1H) 4.96-4.87 (m, 1H), 4.55-4.49 pyrrolidin-1-yl]-3,3-dimethyl-1- (m,1H), 4.48-4.34 (m, 2H), 4.31-4.21 (m, 2H),oxobutan-2-yl]carbamoyl]pentyl) 4.09-3.96(m, 2H), 3.95-3.81 (m, 2H),3.76-3.66 phenoxy]butan-2-yl]carbamoyl]- (m, 2H), 3.63-3.59 (m, 2H),3.46-3.27 (m, 3H), 6-oxo-octahydropyrrolo[l,2- 2.59-2.55 (m, 2H), 2.46(s, 3H), 2.30-2.24 (m, a][1,5]diazocin-5-yl]carbamoyl]- 1H), 2.20 (s,3H), 2.16-1.98 (m, 6H), 1.96-1.62 1H-indole-5- (m, 7H), 1.60-1.44 (m,5H), 1.38 (d, J = 7.0 Hz, carbonylphosphonate 3H), 1.31-1.23 (m, 2H),0.93 (s, 9H) 261 I-276 diammonium 2-[[(2S)-1-[(2S)- [(M − (400 MHz,DMSO-d₆) δ 11.84 (s, 1H), 8.98 (s, 2-[[(2S)-4-carbamoyl-1-[2- 1)]⁻ =1H), 8.87 (s, 1H), 8.75-8.69 (m, 1H), 8.39 (d, J =fluoro-3-(4-[[(2S)-1-[(2S,4R)-4- 1213.05 7.8 Hz, 1H), 7.97-7.93 (m, 1H),7.90-7.86 (m, hydroxy-2-[[(1S)-1-[4-(4- 1H), 7.84-7.80 (m, 1H),7.47-7.29 (m, 6H), 7.20 methyl-1,3-thiazol-5-yl)phenyl] (s, 1H),7.04-6.95 (m, 2H), 6.86-6.75 (m, 2H), ethyl]carbamoyl]pyrrolidin-1-yl]-4.94-4.79 (m, 2H), 4.51 (d, J = 9.3 Hz, 1H), 4.45-3,3-dimethyl-1-oxobutan-2- 4.40 (m 1H) 4.35-4.24 (m, 2H), 4.06-3.98 (m,yl]carbamoyl]butyl)phenoxy] 1H), 4.60-3.8,7 (m, 2H), 3.84-3.77 (m, 1H),3.65- butan-2-yl]carbamoyl]pyrrolidin- 3.57 (m, 3H), 3.47-3.34 (m, 1H),2.62-2.55 (m, 1-yl]-4-methyl-1-oxopentan- 3H), 2.45 (s, 3H), 2.33-2.25(m, 1H), 2.19-2.11 2-yl]carbamoyl]-1H-indole- (m, 3H), 2.07-1.97 (m,3H), 1.93-1.74 (m, 5H), 5-carbonylphosphonate 1.72-1.62 (m, 3H),1.61-1.44 (m, 6H), 1.37 (d, J = 7.0 Hz, 3H), 0.94-0.90 (m, 15H) 267I-277 2-[[(2S,11S)-2-[[(1S)-3-carbamoyl- 1000.35 (400 MHz, DMSO-d₆) δ12.10 (s, 1H), 11.09 (s, 1-(pyridin-2-yl)propyl] 1H), 8.98 (d, J = 8.0Hz, 1H), 8.83 (s, 1H), 8.58- carbamoyl]-6-[6-[1-(2,6- 8.46 (m, 2H),7.99-7.93 (m, 1H), 7.80-7.71 (m, dioxopiperidin-3-yl)-3-methyl-2- 1H),7.57-7.46 (m, 2H), 7.35-7.29 (m, 1H), 7.27-oxo-1,3-benzodiazol-5-yl]hexyl]- 7.19 (m, 2H), 7.06-6.98 (m, 2H),6.95-6.83 (m, 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} 3H),6.72 (s, 1H), 5.38-5.30 (m, 1H), 5.19-5.13[4,13]]trideca-4(13),5,7-trien- (m, 1H), 4.85-4.74 (m, 1H), 4.72-4.62(m, 1H), 11-yl]carbamoyl]-1H-indole- 3.48-3.41 (m, 2H), 3.32 (s, 3H),3.23-3.06 (m, 5-carbonylphosphonic acid 3H), 2.96-2.79 (m, 2H),2.76-2.58 (m, 4H), 2.49- 2.45 (m, 2H), 2.30-2.13 (m, 2H), 2.07-1.85 (m,5H), 1.66-1.49 (m, 4H), 1.38-1.27 (m, 4H) 268 I-2782-[[(5S,8S,10aR)-8-[[(1S)-3- 1167.55 (400 MHz, DMSO-d₆) δ 12.22-12.02(m, 1H), carbamoyl-1- 11.09 (s, 1H), 8.90-8.63 (m, 3H), 8.47-8.41(m,(diphenylmethylcarbamoyl) 1H), 8.26-8.17 (m, 1H), 7.98-7.93 (m, 1H),7.57- propyl]carbamoyl]- 7.51 (m, 1H), 7.48-7.40 (m, 1H), 7.38-7.20 (m,6-oxo-3-[3-[(1r,4r)-4-[1-(2,6- 10H), 7.11-7.05 (m, 1H), 7.03-6.96 (m,1H), dioxopiperidin-3-yl)-3-methyl- 6.94-6.87 (m, 1H), 6.81-6.71 (m,1H), 6.13-6.07 2-oxo-1,3-benzodiazol-5-yl] (m, 1H), 5.37-5.29 (m, 1H),5.05-4.87 (m, 1H), cyclohexyl]propanoyl]- 4.51-4.42 (m, 1H), 4.41-4.32(m, 1H), 4.27-4.17 octahydropyrrolo[1,2-a][1,5] (m, 1H), 4.06-3.89 (m,1H), 3.86-3.75 (m, 1H), diazocin-5-yl]carbamoyl]-1H- 3.72-3.60 (m, 1H),3.57-3.45 (m, 1H), 3.33 (s, indole-5-carbonylphosphonic 3H), 2.90-2.85(m, 1H), 2.76-2.54 (m, 5H), 2.24- acid 1.87 (m, 8H), 1.85-1.56 (m, 16H)269 I-279 diammonium 2-[[(2S)-1-[(2S)- 1228.65 (400 MHz, CD₃OD) δ9.00-8.96 (m, 1H), 8.89 2-[[(2S)-4-carbamoyl-1-[2- (s, 1H), 8.58 (d, J =7.6 Hz, 1H), 8.18 (d, J = 8.7 fluoro-3-(5-[[(2S-1-[(2S,4R)- Hz, 1H),8.13-8.06 (m, 1H), 7.52-7.39 (m, 5H), 4-hydroxy-2-[[(1S)-1-[4-(4-7.00-6.94 (m, 1H), 6.85-6.79 (m, 1H), 5.06-4.91methyl-1,3-thiazol-5-yl)phenyl] (m, 2H), 4.67-4.56 (m, 2H), 4.46-4.42(m, 2H), ethyl]carbamoyl]pyrrolidin-1- 4.29-4.20 (m, 1H), 4.14-3.95 (m,3H), 3.93-3.86 yl]-3,3-dimethyl-1-oxobutan-2- (m, 1H), 3.79-3.69 (m,2H), 3.63-3.34 (m, 4H), yl]carbamoyl]pentyl)phenoxy] 2.67-2.65 (m, 2H),2.50 (s, 3H), 2.42-2.18 (m, butan-2-yl]carbamoyl]pyrrolidin- 6H),2.17-1.90 (m, 4H), 1.90-1.78 (m, 3H), 1.74- 1-yl]-4-methyl-1-oxopentan-1.60 (m, 4H), 1.54-1.48 (m, 3H), 1.42-1.27 (m,2-yl]carbamoyl]-1H-indole- 2H), 1.09-0.99 (m, 13H) 5-carbonylphosphonate270 I-280 diammonium 2-[[(2S,11S)-2- 1227.60 (300 MHz, DMSO-d₆) δ 11.88(s, 1H), 9.94 (s, [[(1S-3-carbamoyl-1-[[3-(4- 1H), 9.08-8.86 (m, 3H),8.47-8.29 (m, 2H), 7.96 [[(2S)-1-[(2S,4R)-4-hydroxy-2- (d, J = 8.7 Hz,1H), 7.87-7.78 (m, 1H), 7.49-7.37 [[(1S)-1-[4-(4-methyl-1,3- (m, 7H),7.36-7.30 (m, 1H), 7.22-7.08 (m, 4H), thiazol-5-yl)phenyl]ethyl]7.06-6.95 (m, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.79carbamoyl]pyrrolidin-1-yl]-3,3- (s, 1H), 5.25-5.12 (m, 2H), 4.97-4.86(m, 1H), dimethyl-1-oxobutan-2-yl] 4.73-4.67 (m, 1H), 4.57-4.40 (m, 2H),4.36-4.27 carbamoyl]butyl)phenyl]carbamoyl] (m, 2H), 3.65-3.50 (m, 4H),3.08-2.97 (m, 2H), propyl]carbamoyl]-12-oxo-1- 2.47 (s, 3H), 2.36-2.22(m, 4H), 2.21-2.10 (m, azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]3H), 2.06-1.77 (m, 5H), 1.58-1.47 (m, 4H), 1.39trideca-4(13),5,7-trien-11-yl] (d, J = 6.9 Hz, 3H), 1.29-1.15 (m, 2H),0.95 (s, carbamoyl]-1H-indole-5- 9H) carbonylphosphonate 271 I-281diammonium 2-[[(2S,11S)-2- 1248.85 (400 MHz, DMSO-d₆) δ 11.90 (s, 1H),9.03-8.93 [(2S)-4-carbamoyl-1-[2-fluoro- (m, 2H), 8.90 (s, 1H), 8.42 (d,J = 7.8 Hz, 1H), 3-[4-([[(2S)-1-[(2S,4R)-4- 8.18-8.12 (m, 1H), 7.96 (d,J = 8.4 Hz, 1H), 7.49- hydroxy-2-[[(1S)-1-[4-(4- 7.40 (m, 4H), 7.38 (d,J = 8.1 Hz, 2H), 7.27 (s, methyl-1,3-thiazol-5-yl)phenyl] 1H), 7.09 (t,J = 7.7 Hz, 2H), 7.03-6.90 (m, 4H), ethyl]carbamoyl]pyrrolidin-1-yl]-6.88-6.79 (m, 1H), 6.76 (s, 1H), 5.13-5.06 (m,3,3-dimethyl-1-oxobutan-2-yl] 1H) 4.95-4.86 (m 1H), 4.76-4.64 (m, 1H),4.49- carbamoyl]oxy)butyl]phenoxy] 4.41 (m, 1H), 4.31-4.25 (m, 1H), 4.17(d, J = 9.2 butan-2-yl]carbamoyl]-12- Hz, 1H), 4.05-3.93 (m, 5H),3.62-3.57 (m, 2H), oxo-1-azatricyclo[6.4.1.0{circumflex over ( )}[4,13]]3.50-3.43 (m, 3H), 3.22-3.09 (m, 3H), 2.94-2.84trideca-4(13),5,7-trien-11- (m, 1H), 2.65-2.58 (m, 2H), 2.46 (s, 3H),2.32- yl]carbamoyl]-1H-indole-5- 2.19 (m, 2H), 2.18-2.09 (m, 2H),2.07-2.00 (m, carbonylphosphonate 1H), 1.88-1.66 (m, 3H), 1.65-1.50(m,4H), 1.37 (d, J = 7.0 Hz, 3H), 0.94 (s, 9H) 272 I-283 diammonium2-[[(2S,11S)-2- [(M − (300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.01-8.90[(2S)-4-carbamoyl-1-[2-chloro- 1)]⁻ = (m, 3H), 8.84 (s, 1H), 8.16 (d, J= 7.4 Hz, 1H), 3-(3-[[(2S)-1 4(2S,4R)-4- 1244.65 8.05 (d, J = 9.3 Hz,1H), 7.99-7.83 (m, 1H), 7.48- hydroxy-2-([1-[4-(4-methyl-1,3- 7.39 (m,3H), 7.36-7.28 (m, 4H), 7.25-7.14 (m, thiazol-5-yl)phenyl]cyclopropyl]7.12-7.05 (m 2H) 7.06-7.01 (m, 2H), 6.96- carbamoyl)pyrrolidin-1-yl]-6.87, (m, 1H), 6.7,8 (s, 1H), 5.14-5.07 (m, 1H),3,3-dimethyl-1-oxobutan-2-yl] 4.73-4.67 (m, 1H), 4.63-4.56 (m, 1H),4.46-4.38 carbamoyl]propyl)phenoxy] (m, 2H), 4.08-3.92 (m, 3H),3.70-3.65 (m, 2H), butan-2-yl]carbamoyl]-12- 3.22-3.10 (m, 3H),3.02-2.93 (m, 1H), 2.79-2.59 oxo-1-azatricyclo[6.4.1.0{circumflex over( )}[4,13]] (m, 3H), 2.45 (s, 3H), 2.39-2.09 (m, 7H), 2.07-trideca-4(13),5,7-trien-11-yl] 1.97 (m, 1H), 1.96-1.66 (m, 6H),1.29-1.10 (m, carbamoyl]-1H-indole-5- 4H), 0.97 (s, 9H)carbonylphosphonate 273 I-284 diammonium 2-[[(5S,8S,10aR)- 1269.50 (300MHz, DMSO-d₆) δ 12.08-11.74 (m, 1H), 3-acetyl-8-[[(2S)-4-carbamoyl-9.001 (s, 1H), 8.95-8.90 (m, 1H), 8.86-8.79 (m,1-[2-chloro-3-(3-[[(2S)-1- 1H), 8.56-8.47 (m, 1H), 8.13-7.92 (m, 3H),7.43 [(2S,4R)-4-hydroxy-2-([1-[4- (d, J = 8.4 Hz, 1H), 7.37-7.29 (m,5H), 7.26-7.18 (4-methyl-1,3-thiazol-5-yl) (m, 1H), 7.07-6.97 (m, 1H),6.95-6.88 (m, 1H), phenyl]cyclopropyl]carbamoyl) 6.82 (s, 1H), 6.71 (s,1H), 5.07-5.01 (m, 1H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.64-4.52 (m,1H), 4.44-4.21 (m, 4H), 4.14-3.99 oxobutan-2-yl]carbamoyl] (m, 2H),3.98-3.83 (m, 3H), 3.77-3.64 (m, 5H), propyl)phenoxy]butan-2-yl]2.76-2.62 (m, 3H), 2.45 (s, 3H), 2.40-2.28 (m,carbamoyl]-6-oxo-octahydropyrrolo 2H), 2.27-2.08 (m, 7H), 2.07-1.85 (m,5H), 1.85- [1,2-a][1,5]diazocin-5-yl] 1.63 (m, 6H), 1.26-1.16 (m, 4H),0.96 (s, 9H) carbamoyl]-1H-indole-5- carbonylphosphonate 274 I-285(2-(((5S,8S,10aR)-8-(((S)-5- [(M − (400 MHz, DMSO-d₆) δ 12.21-12.0 (m,1H), amino-1-((4-(methylsulfonyl) 1)]⁻ = 11.09 (s, 1H), 8.82 (s, 2H),8.61-8.43 (m, 2H), benzyl)amino)-1,5-dioxopentan- 1168.05 8.32 (d, J =8.1 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 2-yl)carbamoyl)-3-((1s,4S)- 7.86(d, J = 8.1 Hz, 2H), 7.60-7.38 (m, 4H), 7.06-4-(2-(1-(2,6-dioxopiperidin-3- 6.95 (m, 2H), 6.94-6.76 (m, 2H), 5.34(dd, J = yl)-3-methyl-2-oxo-2,3-dihydro- 12.6, 5.3 Hz, 1H), 5.04-5.01(m, 1H), 4.45 (t, J = 1H-benzo[d]imidazol-5- 8.1 Hz, 1H), 4.40 (d, J =6.0 Hz, 2H), 4.25-4.21 yl)ethyl)cyclohexane-1-carbonyl)- (m, 2H),3.59-3.48 (m, 3H), 3.42-3.31 (m, 5H), 6-oxodecahydropyrrolo 3.30 (s,3H), 3.21 (s, 3H), 2.98-2.81 (m, 2H), [1,2-a][1,5]diazocin-5-yl)2.78-2.61 (m, 3H), 2.28-2.11 (m, 4H), 2.09-1.96carbamoyl)-1H-indole-5-carbonyl) (m, 2H), 1.89-1.65 (m, 10H), 1.51-1.44(m, 3H), phosphonic acid 1.35-1.20 (m, 2H). 275 I-2862-[[(5S,8S,10aR)-8-[[(1S)-3- 1170.35 (300 MHz, DMSO-d₆) δ 12.23-12.01(m, 1H), carbamoyl-1-[[(4- 11.10 (s, 1H), 8.81 (s, 1H), 8.61-8.50 (m,1H), methanesulfonylphenyl) 8.45 (d, J = 6.8 Hz, 1H), 8.28 (dd, J =15.8, 7.6 methyl]carbamoyl] Hz, 1H), 7.97 (dd, J = 9.0, 1.6 Hz, 1H),7.87 (dd, propyl]carbamoyl]-6-oxo-3- J = 8.3, 2.9 Hz, 2H), 7.60-7.40 (m,4H), 7.32- [2-[(1r,4r)-4-[[1-(2,6-dioxopiperidin- 7.24 (m, 1H),7.06-6.91 (m, 2H), 6.87-6.68 (m, 3-yl)-3-methyl-2-oxo- 2H), 5.35 (dd, J= 12.8, 5.4 Hz, 1H), 5.01-4.84 1,3-benzodiazol-5-yl]methyl] (m, 1H),4.51-4.35 (m, 4H), 4.31-4.11 (m, 4H),cyclohexyl]acetyl]-octahydropyrrolo 3.96-3.86 (m, 2H), 3.82-3.78 (m,1H), 3.33 (s, [1,2-a][1,5]diazocin-5- 3H), 3.20 (s, 3H), 2.77-2.63 (m,3H), 2.31-1.95 yl]carbamoyl]-1H-indole-5- (m, 8H), 1.93-1.60 (m, 12H),1.53-1.46 (m, 1H), carbonylphosphonic acid; 1.09-0.87 (m, 4H)trifluoroacetic acid 276 I-288 2-[[(5S,8S,10aR)-8-[[(1S)-3- 1143.40 (400MHz, DMSO-d₆) δ 12.21-12.01 (m, 1H), carbamoyl-1-[[(4- 11.09 (s, 1H),8.87-8.79 (m, 1H), 8.59-8.53 (m, methanesulfonylphenyl)methyl] 1H),8.48-8.40 (m, 1H), 8.29 (dd, J = 22.4, 7.6carbamoyl]propyl]carbamoyl]-3-[7-[1- Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H),7.86 (dd, J = (2,6-dioxopiperidin-3-yl)-3- 8.4, 2.4 Hz, 2H), 7.51 (m,3H), 7.43 (d, J = 11.2 methyl-2-oxo-1,3-benzodiazol- Hz 1H) 7.27 (d, J =17.5 Hz, 1H), 7.05-6.97 (m, 5-yl]heptanoyl]-6-oxo- 2H), 6.87-6.84 (m,2H), 5.35 (dd, J = 12.8, 5.4 octahydropyrrolo[1,2-a][1,5]diazocin- Hz,1H), 5.01-4.94 (m, 1H), 4.48-4.37 (m, 3H), 5-yl]carbamoyl]-1H-indole-4.29-4.20 (m, 2H), 3.96-3.73 (m, 4H), 3.65-3.50 5-carbonylphosphonicacid (m, 3H), 3.31 (s, 3H), 3.21 (s, 3H), 2.95-2.85 (m, 1H), 2.77-2.57(m, 5H), 2.22-2.09 (m, 3H), 2.03- 1.77 (m, 6H), 1.71-1.51 (m, 6H),1.43-1.28 (m, 4H)

Example 277. Ammonium2-[[(2S,11S)-2-[[(3S,4R)-1-carbamoyl-4-[[4-(4-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]butyl)phenyl]methoxy]pentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]-1H-indole-5-carboxylate(I-131)

To a solution of(2S,4R)-1-[(2S)-2-[5-[4-([[(2R,3S)-3-[[(2S,11S)-11-amino-12-oxo-1-azatricyclo[6.4.1.0{circumflexover( )}[4,13]]trideca-4(13),5,7-trien-2-yl]formamido]-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]pentanamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide(200.00 mg, 0.202 mmol) and5-[(diethoxyphosphoryl)carbonyl]-1H-indole-2-carboxylic acid (78.75 mg,0.242 mmol) in DMA (5.00 mL) were added TEA (61.25 mg, 0.605 mmol) andPyBOP (136.50 mg, 0.262 mmol) at 25° C. The solution was stirred at 25°C. for 4 h. To above resulting solution was added a solution of NaHCO₃(84.75 mg, 1.009 mmol) in H₂O (5.00 mL). The resulting mixture wasstirred for additional 16 h at 25° C. The crude reaction solution waspurified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column, 30×150 mm, 5 um; Mobile Phase A: water (plus 10moL/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5 Bto 35 B in 7 min; Detector: 220/254 nm; Desired fractions were collectedat 6.3 min, concentrated and lyophilized to afford the title compound asa white solid (30.5 mg, 13%): ¹H NMR (400 MHz, CD₃OD) δ 8.90 (s, 1H),8.43 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.48-7.37(m, 4H), 7.36-7.31 (m, 1H), 7.24 (d, J=7.8 Hz, 2H), 7.18-6.99 (m, 5H),5.21-5.17 (m, 1H), 5.01 (q, J=7.1 Hz, 1H), 4.83-4.80 (m, 1H), 4.68-4.54(m, 2H), 4.54-4.40 (m, 3H), 4.04-3.99 (m, 1H), 3.91-3.88 (m, 1H),3.78-3.74 (m, 1H), 3.68-3.45 (m, 3H), 3.28-3.22 (m, 1H), 3.18-3.02 (m,1H), 2.61-2.57 (m, 2H), 2.49 (s, 3H), 2.46-2.14 (m, 6H), 2.06-1.93 (m,2H), 1.78-1.54 (m, 5H), 1.51 (d, J=7.0 Hz, 3H), 1.41-1.29 (m, 1H), 1.21(d, J=6.3 Hz, 3H), 1.04 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=1178.65.

The following compounds in Table 75 were synthesized according to theprocedure to prepare I-131.

TABLE 75 Characterization Data for Exemplary STAT3 Degraders EXAM- MS:PLE I-# Chemical Name [(M + 1)]⁺ ¹H NMR 278 I-2872-[[(5S,8S,10aR)-8-[[(1S)-3- [(M − H)]⁻ = (400 MHz, DMSO-d₆) δ12.21-12.01 carbamoyl-1-[[(4- 1103.50 (m, 1H), 11.09 (s, 1H), 8.58 (s,1H), methanesulfonylphenyl)methyl] 8.60-8.51 (m, 1H), 8.48-8.44 (m, 1H),carbamoyl]propyl]carbamoyl]-6- 8.36-8.32 (m, 1H), 7.87 (d, J = 8.3 Hz,oxo-3-[2-[(1s,4s)-4-[[1-(2,6- 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.55-7.45dioxopiperidin-3-yl)-3-methyl-2- (m, 3H), 7.37 (d, J = 7.3 Hz, 1H), 7.27oxo-1,3-benzodiazol-5- (d, J = 16.5 Hz, 1H), 6.99-6.95 (m, 2H),yl]methyl]cyclohexyl]acetyl]- 6.84-6.80 (m 2H) 5.33 (dd, J = 12.7,octahydropyrrolo[1,2- 5.8 Hz, 1H), 5.03-4.98 (m, 1H), 4.46-a][1,5]diazocin-5-yl]carbamoyl]- 4.40 (m, 3H), 4.30-4.23 (m, 2H), 3.99-1H-indole-5-carboxylic acid 3.75 (m, 3H), 3.33 (s, 3H), 3.29 (s, 2H),3.19 (s, 3H), 2.93-2.89 (m, 2H), 2.86- 2.59 (m, 5H), 2.16-2.05 (m, 3H),2.04- 2.70 (m, 10H), 1.55-1.35 (m, 8H)

Example 279.(2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2-((1S,4R)-4-((1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphonicacid (I-234)

Step 1. diethyl(2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2-((1S,4R)-4-((1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphonate.To a stirred mixture of(2S)-2-[[(5S,8S,10aR)-5-amino-6-oxo-3-[2-[(1s,4s)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin-8-yl]formamido]-N-(diphenylmethyl)pentanediamide(500 mg, 0.55 mmol) and5-[(diethoxyphosphoryl)carbonyl]-1H-indole-2-carboxylic acid (213 mg,0.66 mmol) in DMA (8 mL) were added PyBOP (426 mg, 0.82 mmol) and TEA(276 mg, 2.73 mmol) at room temperature. After stirring for additional 1h, the resulting mixture was purified by reverse phase flashchromatography with the following conditions: Column: WelFlash™ C18-I,20-40 um, 330 g; Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN;Gradient: 35%-55% B in 25 min; Flow rate: 80 mL/min; Detector: UV220/254 nm; Desired fractions were collected at 53% B and concentratedunder reduced pressure to afford the title compound (520 mg, 78%) as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.34-12.18 (m, 1H), 11.10 (s,1H), 8.90-8.69 (m, 2H), 8.50 (d, J=6.8 Hz, 1H), 8.33-8.12 (m, 1H), 7.96(dd, J=8.9, 1.7 Hz, 1H), 7.66-7.54 (m, 1H), 7.50 (s, 1H), 7.39-7.19 (m,13H), 7.04-6.91 (m, 2H), 6.88-6.75 (m, 2H), 6.11 (dd, J=8.5, 3.3 Hz,1H), 5.37-5.31 (m, 1H), 5.01-4.87 (m, 1H), 4.51-4.32 (m, 3H), 4.26-4.13(m, 5H), 4.06-3.94 (m, 1H), 3.82-3.74 (m, 2H), 3.35 (s, 3H), 3.28 (s,2H), 2.98-2.81 (m, 1H), 2.76-2.54 (m, 5H), 2.22-1.56 (m, 10H), 1.48-1.42(m, 7H), 1.35-1.28 (m, 8H); LC/MS (ESI, m/z): [(M+H)]⁺=1223.40.

The intermediates in Table 76 were prepared according to the procedureto prepare Intermediate S.

TABLE 76 Characterization data for intermediates prepared according toabove. Inter- MS: mediate Structure Chemical Name [(M + 1)]⁺ ¹H-NMR S1

diethyl 2- [[(2S,11S)-2-[[(2S)- 4-carbamoyl-1-[2- fluoro-3-(3-[[(2S)-1-[(2S,4R)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl] carbamoyl]pyrrolidin- 1-y1]-3,3-dimethyl- 1-oxobutan-2-yl]carbamoyl] propyl)-5- methylphenoxy]butan- 2-yl]carbamoyl]- 12-oxo-1-azatricyclo[6.4.1.0{circumflex over ( )} [4,13]]trideca-4(13),5,7-trien-11- yl]carbamoyl]-1H- indole-5- carbonylphosphonate1288.50 (300 MHz, DMSO-d₆) δ 12.24 (s, 1H), 9.04-8.95 (m, 2H), 8.77-8.72(m, 1H), 8.45-8.33 (m, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 9.1Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.51 (s,1H), 7.40 (q, J = 8.3 Hz, 4H), 7.26- 7.21 (m, 1H), 7.12-7.04 (m, 2H),7.01-6.94 (m, 1H), 6.79 (d, 1H), 6.59 (d, J = 5.9 Hz, 1H), 5.10-5.03 (m,1H), 4.94-4.87 (m, 1H), 4.74-4.63 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H),4.41 (t, J = 8.1 Hz, 1H), 4.30-4.14 (m, 5H), 4.04-3.88 (m, 3H), 3.63-3.57 (m, 2H), 3.19-3.10 (m, 2H), 2.97-2.77 (m, 5H), 2.45 (s, 3H),2.33-2.23 (m, 2H), 2.21 (s, 3H), 2.06-1.92 (m, 4H), 1.86- 1.66 (m, 6H),1.36 (s, 3H), 1.29 (t, J = 7.0 Hz, 6H), 0.94 (s, 9H) S2

diethyl 2- [[(5S,8S,10aR)-3- acety1-8-[[(2S)-4- carbamoyl-1-[2-fluoro-3-(4-[[(2S)- 1-[(2S,4R)-4- hydroxy-2-[[(1S)-1- [4-(4-methyl-1,3-thiazol-5- yl)phenyl]ethyl] carbamoyl]pyrrolidin- 1-y1]-3,3-dimethyl-1-oxobutan-2- yl]carbamoyl]butyl)- 5- methylphenoxyl]butan-2-yl]carbamoyl]- 6-oxo- octahydropyrrolo[1, 2-a][1,5]diazocin-5-yl]carbamoyl]-1H- indole-5- carbonylphosphonate 1326.60 (400 MHz,DMSO-d₆) δ 12.43- 12.10 (m, 1H), 8.97 (s, 1H), 8.78-8.71 (m, 1H), 8.50(d, J = 6.9 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.09-7.90 (m, 2H), 7.80(d, J = 9.2 Hz, 1H), 7.59-7.47 (m, 2H), 7.40 (q, J = 8.3 Hz, 4H), 7.22(d, J = 9.7 Hz, 1H), 6.86- 6.75 (m, 2H), 6.68-6.57 (m, 1H), 5.08 (d, J =3.5 Hz, 1H), 5.04-4.95 (m, 1H), 4.92 (q, J = 7.3 Hz, 1H), 4.55-4.31 (m,4H), 4.30-4.11 (m, 6H), 4.09-3.93 (m, 2H), 3.92-3.66 (m, 4H), 3.65-3.53(m, 2H), 2.45 (s, 3H), 2.33-2.25 (m, 1H), 2.22 (s, 3H), 2.21-2.05 (m,7H), 2.04-1.92 (m, 3H), 1.91-1.61 (m, 7H), 1.58-1.45 (m, 4H), 1.37 (s,3H), 1.33-1.24 (m, 7H), 0.92 (s, 9H) S3

diethyl 2- [(5S,8S,10aR)-8- [[(1S)-3-carbamoyl- 1-(diphenylmethylcarbamoyl) propyl]carbamoyl]- 6-oxo-3-[2-[(1s,4s)-4-[[1-(2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]- octahydropyrrolo[1,2-a][1,5]diazocin- 5-yl]carbamoyl]- 1H-indole-5- carbonylphosphonate1223.85 (300 MHz, DMSO-d₆) δ 12.35- 12.18 (m, 1H), 11.09 (s, 1H),8.90-8.69 (m, 2H), 8.51 (d, J = 6.8 Hz, 1H), 8.27-8.16 (m, 1H), 7.97(dd, J = 8.9, 1.7 Hz, 1H), 7.63-7.56 (m, 1H), 7.52-7.50 (m, 1H),7.42-7.14 (m, 13H), 7.07-6.91 (m, 2H), 6.91-6.66 (m, 2H), 6.12 (dd, J =8.4, 2.2 Hz, 1H), 5.38-5.31 (m, 1H), 5.00-4.88 (m, 1H), 4.55-4.32 (m,3H), 4.26-4.15 (m, 5H), 3.97-3.75 (m, 1H), 3.35 (s, 3H), 3.30 (s, 2H),2.96-2.87 (m, 1H), 2.78-2.55 (m, 5H), 2.25-1.57 (m, 10H), 1.52-1.40 (m,7H), 1.35-1.28 (m, 8H) S4

diethyl 2- [[(5S,8S,10aR)-8- [[(1S)-3-carbamoyl- 1-([[4-(propane-2-sulfonyl)phenyl] methyl]carbamoyl) propyl]carbamoyl]-6-oxo-3-[2-[(1s,4s)-4- [[1-(2,6 dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]methyl]cyclohexyl] acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin- 5-yl]carbamoyl]- 1H-indole-5- carbonylphosphonate1253.60 (400 MHz, DMSO-d₆) δ 12.34- 12.17 (m, 1H), 11.09 (d, J = 2.5 Hz,1H), 8.75 (dd, J = 5.1, 1.7 Hz, 1H), 8.58-8.52 (m, 2H), 8.30 (dd, J =17.7, 7.4 Hz, 1H), 7.96 (dd, J = 8.8, 1.8 Hz, 1H), 7.79 (d, J = 8.2 Hz,2H), 7.61 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 8.5, 2.0 Hz, 3H), 7.27 (d,J = 14.8 Hz, 1H), 7.04-6.93 (m, 2H), 6.89-6.77 (m, 2H), 5.37- 5.31 (m,1H), 4.99-4.87 (m, 1H), 4.49-4.37 (m, 3H), 4.32- 4.14 (m, 6H), 4.02-3.72(m, 2H), 3.42-3.38 (m, 2H), 3.33 (s, 2H), 3.29 (s, 2H), 2.90 (t, J =14.8 Hz, 1H), 2.78-2.54 (m, 6H), 2.24-2.11 (m, 3H), 2.07- 1.60 (m, 10H),1.48-1.45 (m, 8H), 1.30 (t, J = 7.0, 6H), 1.14 (dd, J = 6.8, 2.1 Hz, 6H)S5

diethyl 2- [[(5S,8S,10aR)-8- [[(1S)-3-carbamoyl- 1-[[(4-methanesulfonylphenyl) methyl] carbamoyl]propyl] carbamoyl]-6-oxo-3-[(1s,4s)-4-[2-[1- (2,6- dioxopiperidin-3- yl)-3-methyl-2-oxo-1,3-benzodiazol-5- yl]ethyl] cyclohexanecarbonyl]- octahydropyrrolo[1,2-a][1,5]diazocin- 5-yl]carbamoyl]- 1H-indole-5- carbonylphosphonate1225.50 (300 MHz, DMSO-d₆) δ 12.31 (s, 1H), 11.08 (s, 1H), 8.87-8.71 (m,1H), 8.57 (d, J = 5.9 Hz, 1H), 8.55-8.41 (m, 1H), 8.32 (q, J = 11.5,10.2 Hz, 1H), 7.95 (dd, J = 8.8, 1.7 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H),7.65-7.55 (m, 1H), 7.54-7.47 (m, 3H), 7.32- 7.17 (m, 1H), 7.08-6.91 (m,2H), 6.91-6.76 (m, 2H), 5.34 (dd,J = 12.6, 5.6 Hz, 1H), 5.04- 4.91 (m,1H), 4.89-4.75 (m, 1H), 4.43 (dd, J = 20.0, 7.0 Hz, 3H), 4.31-4.10 (m,7H), 3.94 (d, J = 13.5 Hz, 1H), 3.87-3.71 (m, 1H), 3.46 (d, J = 2.2 Hz,1H), 3.33 (s, 3H), 3.18 (s, 3H), 3.06- 2.81 (m, 2H), 2.78-2.54 (m, 4H),2.28-2.10 (m, 4H), 2.01- 1.78 (m, 6H), 1.72-1.45 (m, 11H), 1.29 (t, J =7.0 Hz, 6H) S6

diethyl (2- (((5S,8S,10aR)-8- (((5)-5-amino-1- ((4- isopropylbenzyl)amino)-1,5- dioxopentan-2- yl)carbamoyl)-3- ((1r,4R)-4-(2-(1- (2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-5- yl)ethyl)cyclohexane- 1-carbonyl)-6- oxodecahydropyrrolo [1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H- indole-5- carbonyl)phosphonate1189.50 (300 MHz, DMSO-d₆) δ 12.32- 12.12 (m, 1H), 11.08 (s, 1H),8.77-8.70 (m, 1H), 8.47-8.39 (m, 1H), 8.37-8.30 (m, 1H), 8.28-8.18 (m,1H), 7.99-7.89 (m, 1H), 7.64-7.54 (m, 1H), 7.47 (s, 1H), 7.29-7.21 (m,1H), 7.15 (s, 4H), 7.08-6.81 (m, 3H), 6.78 (s, 1H), 5.39-5.27 (m, 1H),5.01-4.90 (m, 1H), 4.88-4.69 (m, 1H), 4.49-4.37 (m, 1H), 4.28-4.10 (m,9H), 3.98-3.87 (m, 1H), 3.80-3.69 (m, 1H), 3.49-3.42 (m, 2H), 3.31 (s,3H), 3.03-2.95 (m, 1H), 2.93-2.73 (m, 2H), 2.66-2.56 (m, 3H), 2.24-2.08(m, 4H), 2.03-1.72 (m, 6H), 1.71-1.46 (m, 11H), 1.29 (t, J = 7.0 Hz,6H), 1.19- 1.13 (m, 6H).

Step 2:(2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2-((1S,4R)-4-((1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphonicacid. To a stirred solution of diethyl2-[[(5S,8S,10aR)-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-3-[2-[(1s,4s)-4-([1-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl)cyclohexyl]acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5-carbonylphosphonate(500 mg, 0.41 mmol) in DCM (10 mL) was added bromotrimethylsilane (1.0g, 6.54 mmol) dropwise at room temperature. The resulting mixture wasstirred for 16 h at 40° C. under air atmosphere. The mixture was cooleddown to room temperature and concentrated under reduced pressure. Theresidue was purified by reverse phase flash chromatography with thefollowing conditions: Column: WelFlash™ C18-I, 20-40 um, 120 g; EluentA: Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 15%-35% B in 25min; Flow rate: 60 mL/min; Detector: UV 220/254 nm; desired fractionswere collected at 36% B, concentrated under reduced pressure andlyophilized to afford the title compound (104 mg, 22%) as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 12.3-11.95 (m, 1H), 11.11-11.07 (m, 1H),8.85-8.75 (m, 2H), 8.51-8.45 (m, 1H), 8.29-8.17 (m, 1H), 7.97 (d, J=8.8Hz, 1H), 7.54-7.47 (m, 1H), 7.47-7.38 (m, 1H), 7.34-7.26 (m, 12H),7.06-6.94 (m, 2H), 6.88-6.71 (m, 2H), 6.13-6.08 (m, 1H), 5.39-5.29 (m,1H), 4.99-4.88 (m, 1H), 4.46 (t, J=8.5 Hz, 1H), 4.42-4.30 (m, 1H),4.22-4.13 (s, 1H), 3.95 (d, J=13.7 Hz, 1H), 3.85-3.73 (m, 1H), 3.64-3.51(m, 1H), 3.34-3.24 (m, 4H), 2.93-2.86 (m, 2H), 2.76-2.57 (m, 5H),2.19-1.66 (m, 13H), 1.46-1.35 (m, 9H); LC/MS (ESI, m/z):[(M+H)]⁺=1168.40.

The following compounds in Table 77 were synthesized according to theprocedure to prepare I-234.

TABLE 77 Characterization Data for Exemplary STAT3 Degraders EXAMPLE I-#Chemical Name MS: [(M + 1)]⁺ ¹H NMR 280 I-235 diammonium 2-[[(2S,11S)-2-1232.45 (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 8.98-8.92[[(2S)-4-carbamoyl-1-[2-fluoro- (m, 2H), 8.12 (d,J = 7.9 Hz, 1H), 8.06(d,J = 7.8 3-(3-[[(2S)-1-[(2S,4R)-4- Hz, 2H), 7.98-7.92 (m, 1H),7.46-7.23 (m, 8H), hydroxy-2-[[(1S)-1-[4-(4-methyl- 7.13-7.04 (m, 2H),7.02-6.94 (m, 1H), 6.81-6.73 1,3-thiazol-5-yl)phenyl]ethyl] (m, 2H),6.49 (d, J = 6.0 Hz, 1H), 5.08 (dd, J = carbamoyl]pyrrolidin-1-yl]-3,3-10.7, 3.0 Hz, 1H), 4.88 (p, J = 7.2 Hz, 1H), 4.72-dimethyl-1-oxobutan-2-yl] 4.64 (m, 1H), 4.41-4.29 (m, 3H), 3.98-3.78 (m,carbamoyl]propyl)-5-methyl- 4H), 3.56-3.42 (m, 4H), 3.22-3.08 (m, 4H),2.91- phenoxy]butan-2-yl]carbamoyl]- 2.85 (m, 1H), 2.47 (s, 3H),2.30-2.21 (m, 4H), 12-oxo-1-azatricyclo[6.4.1. 2.18-1.99 (m, 7H),1.97-1.86 (m, 1H), 1.87-1.79 0{circumflex over( )}[4,13]]trideca-4(13),5,7- (m, 1H), 1.73-1.56 (m, 3H), 1.38 (d, J =7.0 Hz, trien-11-yl]carbamoyl]-1H-indole- 3H), 0.99 (s, 9H)5-carbonylphosphonate 281 I-236 diammonium 2-[[(5S,8S,10aR)- 1269.60(400 MHz, DMSO-d₆) δ 12.10-11.79 (m, 1H), 3-acetyl-8-[[(2S)-4-carbamoyl-8.99 (s, 1H), 8.96-8.90 (m, 1H), 8.68-8.55 (m,1-[2-fluoro-3-(4-[[(2S)-1- 1H), 8.45 (d, J = 7.0 Hz, 1H), 8.19-8.00 (m,2H), [(2S,4R)-4-hydroxy-2-[[(1S)-1- 7.98-7.92 (m, 1H), 7.47-7.38 (m,5H), 7.33 (s, [4-(4-methyl-1,3-thiazol-5-yl) 1H), 7.30-7.23 (m, 1H),6.87-6.76 (m, 2H), 6.63- phenyl]ethyl]carbamoyl] 6.56 (m, 1H), 5.18 (s,1H), 5.06-4.90 (m, 2H), pyrrolidin-1-yl]-3,3-dimethyl-1- 4.47-4.32 (m,1H), 4.30-4.21 (m, 1H), 4.20-4.12 oxobutan-2-yl]carbamoyl]butyl)- (m,1H), 4.09-3.93 (m, 3H), 3.92-3.79 (m, 3H), 5-methylphenoxy]butan-2-yl]3.76-3.66 (m, 2H), 3.56-3.42 (m, 2H), 3.26-3.08carbamoyl]-6-oxo-octahydro (m, 4H), 3.00-2.91 (m, 1H), 2.45 (s, 3H),2.29- pyrrolo[1,2-a][1,5]diazocin-5- 2.06 (m, 12H), 2.04-1.80 (m, 5H),1.79-1.59 (m, yl]carbamoyl]-1H-indole-5- 3H), 1.54-1.44 (m, 4H), 1.41(d, J = 7.0, 3H), carbonylphosphonate 0.94 (s, 9H) 282 I-242(2-(((5S,8S,10aR)-8-(((S)-5- 1168.40 (400 MHz, DMSO-d₆) δ 12.3-11.95 (m,1H), amino-1-(benzhydrylamino)-1, 11.11-11.07 (m, 1H), 8.85-8.75 (m,2H), 8.51- 5-dioxopentan-2-yl)carbamoyl)- 8.45 (m, 1H), 8.29-8.17 (m,1H), 7.97 (d, J = 8.8 3-(2-((1R,4R)-4-((1-((S)-2, Hz, 1H), 7.54-7.47 (m,1H), 7.47-7.38 (m, 1H), 6-dioxopiperidin-3-yl)-3- 7.34-7.26 (m, 12H),7.06-6.94 (m, 2H), 6.88-6.71 methyl-2-oxo-2,3-dihydro-1H- (m, 2H),6.13-6.08 (m, 1H), 5.39-5.29 (m, 1H), benzo[d]imidazol-5-yl)methyl)4.99-4.88 (m, 1H), 4.46 (t,J = 8.5 Hz, 1H), 4.42-cyclohexyl)acetyl)-6-oxodecahydro- 4.30 (m, 1H), 4.22-4.13 (s, 1H), 3.95(d,J = 13.7 pyrrolo[1,2-a][1,5]diazocin- Hz, 1H), 3.85-3.73 (m, 1H),3.64-3.51 (m, 1H), 5-yl)carbamoyl)-1H-indole- 3.34-3.24 (m, 4H),2.93-2.86 (m, 2H), 2.76-2.57 5-carbonyl)phosphonic acid (m, 5H),2.19-1.66 (m, 13H), 1.46-1.35 (m, 9H) 283 I-2822-[[(5S,8S,10aR)-8-[[(1S)-3- [(M − H)]⁻ = (300 MHz, DMSO-d₆) δ12.26-11.97 (m, 1H), carbamoyl-1-([[4-(propane-2- 1195.60 11.09 (s, 1H),8.92-8.77 (m, 1H), 8.61-8.46 (m, sulfonyl)phenyl]methyl] 2H), 8.37-8.25(m, 1H), 8.01-7.94 (m, 1H), 7.83- carbamoyl)propyl]carbamoyl]-6- 7.75(m, 2H), 7.58-7.50 (m, 3H), 7.48-7.43 (m, oxo-3-[2-[(1s,4s)-4-[[1-(2,6-1H), 7.33-7.24 (m, 1H), 7.04-6.95 (m, 2H), 6.89-dioxopiperidin-3-yl)-3-methyl-2- 6.72 (m, 2H), 5.41-5.27 (m,1H),5.08-4.84 (m, oxo-1,3-benzodiazol-5-yl] 1H), 4.53-4.37 (m, 3H),4.33-4.14 (m, 2H), 4.03- methyl]cyclohexyl]acetyl]-octa- 3.75 (m, 2H),3.42-3.33 (m, 3H), 3.30 (s, 3H), hydropyrrolo[1,2-a][1,5]diazocin-3.00-2.84 (m, 1H), 2.77-2.58 (m, 5H), 2.32-2.115-yl]carbamoyl]-1H-indole- (m, 4H), 2.09-1.96 (m, 4H), 1.94-1.57 (m,7H), 5-carbonylphosphonic acid 1.56-1.22 (m, 9H), 1.15 (d,J = 6.8 Hz,6H) 284 I-294 (2-(((5S,8S,10aR)-8-(((S)-5- [(M − H)]⁻ = (400 MHz,DMSO-d₆) δ 12.23-12.02 (m, 1H), amino-1-((4-(methylsulfonyl) 1167.1011.09 (s, 1H), 8.81 (s, 1H), 8.60-8.52 (m, 1H),benzyl)amino)-1,5-dioxopentan- 8.44 (d, J = 6.2 Hz, 1H), 8.30 (dd, J =14.7, 7.5 2-yl)carbamoyl)-3-((1r,4R)- Hz, 1H), 7.99-7.91 (m, 1H), 7.86(d, J = 8.2 Hz, 4-(2-(1-(2,6-dioxopiperidin-3- 2H), 7.55-7.45 (m, 4H),7.29-7.20 (m, 1H), 7.08- yl)-3-methyl-2-oxo-2,3-dihydro- 6.96 (m 2H)6.96-6.87 (m, 1H), 6.87-6.80 (m, 1H-benzo[d]imidazol-5-yl) 1H), 5.35(dd, J = 12.8, 5.4 Hz, 1H), 5.03-4.98 ethyl)cyclohexane-1-carbon (m,1H), 4.79-4.90 (m, 1H), 4.55-4.37 (m, 3H), yl)-6-oxodecahydropyrrolo[1,4.24-4.15 (m, 3H), 3.95 (d,J = 13.6 Hz, 1H), 3.762-a][1,5]diazocin-5-yl)carbamoyl)- (s, 1H), 3.47-3.30 (m, 4H), 3.19 (s,3H), 3.09- 1H-indole-5-carbonyl) 3.01 (m, 1H), 2.93-2.84 (m, 1H),2.79-2.55 (m, phosphonic acid 4H), 2.26-2.04 (m, 4H), 2.04-1.85 (m, 4H),1.84- 1.73 (m, 5H), 1.70-1.56 (m, 10H) 285 I-295(2-(((5S,8S,10aR)-8-(((S)-5- 1133.60 (400 MHz, DMSO-d₆) δ 12.17-11.97(m, 1H), amino-1-((4-isopropylbenzyl) 11.09 (s, 1H), 8.82 (s, 1H),8.45-8.39 (m, 1H), amino)-1,5-dioxopentan-2-yl) 8.38-8.29 (m, 1H),8.28-8.18 (m, 1H), 8.01-7.94 carbamoyl)-3-((1r,4R)-4-(2-(1- (m, 1H),7.53 (d, J = 8.7 Hz, 1H), 7.48-7.41 (m, (2,6-dioxopiperidin-3-yl)-3-1H), 7.29-7.20 (m, 1H), 7.17 (s, 4H), 7.08-6.98methyl-2-oxo-2,3-dihydro-1H- (m, 2H), 6.95-6.85 (m, 1H), 6.79 (s, 1H),5.39- benzo[d]imidazol-5-yl)ethyl) 5.30 (m 1H) 5.05-4.93 (m, 1H),4.91-4.75 (m, cyclohexane-1-carbonyl)-6-oxo 1H), 4.49-4.40 (m, 1H),4.28-4.16 (m, 4H), 3.98- decahydropyrrolo[1,2-a][1,5] 3.91 (m, 1H),3.84-3.71(m, 2H), 3.48-3.46 (m, diazocin-5-yl)carbamoyl)-1H- 2H), 3.34(s, 3H), 3.07-2.98 (m, 1H), 2.93-2.79 indole-5-carbonyl)phosphonic (m,2H), 2.66-2.58 (m, 3H), 2.23-2.04 (m, 5H), acid 2.04-1.85 (m, 4H),1.83-1.73 (m, 3H), 1.72-1.46 (m, 11H), 1.22-1.13 (m, 6H).

Example 286.4-carbamoyl-2-(3-methyl-2-oxo-5-[[(1s,4s)-4-[2-[(5S,8S,10aR)-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-5-[5-(phosphonocarbonyl)-1H-indole-2-amido]-octahydropyrrolo[1,2-a][1,5]diazocin-3-yl]l-2-oxoethyl]cyclohexyl]methyl]-1,3-benzodiazol-1-yl)butanoicacid (1-255)

4-Carbamoyl-2-(3-methyl-2-oxo-5-[[(1s,4s)-4-[2-[(5S,8S10aR)-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-5-[5-(phosphonocarbonyl)-1H-indole-2-amido]-octahydropyrrolo[1,2-a][1,5]diazocin-3-yl]-2-oxoethyl]cyclohexyl]methyl-1,3-benzodiazol-1-yl)butanoicacid. A mixture of2-[[(5S,8S,10aR)-8-[[(1S)-3-carbamoyl-1-(diphenylmethylcarbamoyl)propyl]carbamoyl]-6-oxo-3-[2-[(1s,4s)-4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]methyl]cyclohexyl]acetyl]-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5-carbonylphosphonicacid (400 mg) in PBS solution (PH=7.35) was stirred for 7 days at 50° C.under air atmosphere. The resulting solution was purified by reversephase flash chromatography with the following conditions: Column:WelFlash™ C18-I, 20-40 um, 120 g; Eluent A: Water (plus 10 mmol/LNH4HCO3); Eluent B: ACN; Gradient: 15%-35% B in 25 min; Flow rate: 60mL/min; Detector: 220/254 nm; desired fractions were collected at 30% B,concentrated under reduced pressure and lyophilized to afford titlecompound (200 mg) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.89(s, 1H), 8.88 (s, 1H), 8.82-8.78 (m, 1H), 8.64-8.48 (m, 1H), 8.32-8.23(m, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.56-7.40 (m, 2H), 7.40-7.17 (m, 15H),7.01-6.62 (m, 5H), 6.11 (dd, J=8.5, 2.5 Hz, 1H), 5.06-4.61 (m, 3H), 4.47(t, J=8.6 Hz, 1H), 4.38 (q, J=7.3 Hz, 1H), 4.29-4.17 (m, 1H), 4.05-3.97(m, 1H), 3.81-3.65 (m, 1H), 3.40-3.21 (m, 5H), 2.63-2.56 (m, 3H),2.44-2.31 (m, 1H), 2.27-1.88 (m, 10H), 1.88-1.55 (m, 4H), 1.51-1.33 (m,9H); LC/MS (ESI, m/z): [(M−H)]⁻=1183.65.

Example 287. Quantitation of STAT3 Degradation in A549 Cells by WesternBlot Analysis

Degradation of total cellular STAT3 protein in A549 was quantitativelymeasured using SDS-PAGE and Western blot analysis. A549 cells (5×10⁵cells/well, 2 mL) were seeded into 6-well plates and were incubated inthe incubator under 5% CO₂ overnight to reach ˜80% confluency. The nextday, the culture medium was changed with 1 ml fresh media. Then, 1 mL ofmedia containing 2× compound solution was added into the well to makethe final concentration of 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM and 0 μM(DMSO). The media was thoroughly mixed and incubated for 24 hours at 37°C. under 5% CO₂. Then, the culture media was removed from the assayplates and the cells were washed with ice-cold PBS twice. To preparecell lysates, 200 ul pre-chilled RIPA lysis buffer (Boston BioProductsBP-115D) with protease/phosphatase inhibitor (Roche 05892791001/Roche04906837001) was added directly into the well to lyse the cells for 20minutes on ice. The cell lysates were then transferred to centrifugetubes. Insoluble part of lysates was removed by centrifuging the lysatesat 13000 rpm for 20 minutes. The supernatant was then collected andmixed with 5× loading buffer (Beyotime Bio P0015) to make the finalsamples for SDS-PAGE analysis. The samples were heated at 100° C. for 10minutes and cool to room temperature before centrifuging at 13000 rpmfor 20 minutes. To analyze the samples by SDS-PAGE, 10 ul samples wereloaded onto SDS-PAGE gel (Novex, WG1403BOX) and the SDS-PAGE gel was runfor 20 minutes at 80 V, then at 120 V for 1.5 hours. The SDS-PAGE gelwas then transferred to nitrocellulose membrane using the wet-transfermethod at 250 mA for 1.5 hours. The membrane was then blocked withLI-COR blocking buffer (LI-COR, 927-50000) for 1 hour and was probedwith primary antibody (mouse anti-STAT3 (124H6) (CST #9139S) 1:2000 ormouse anti-beta-Actin (8H10D10) (CST #3700) 1:10000) at 4° C. overnight.The membrane was then washed three times with TBST buffer and probedwith secondary antibody (anti-mouse IgG (LI-COR, 926-68070), 1:5000) for1 hour at room temperature. The membrane was then scanned on a LI-COROdyssey instrument and was quantified using Image Studio Version 5.2.Concentration at 50% degradation (DC₅₀) was calculated by fitting dosedependent degradation data using a sigmoidal equation using GraphPadPrism Version 8.0.

STAT3 protein degradation in A549 cells for compounds of the inventionare presented in Table 78. The results for STAT3 DC₅₀ include: compoundswere tested up to 30 μM and >50% degradation was seen at 30 μM or below(<30 μM); compounds were tested up to 30 μM and <50% degradation wasseen at all concentrations (>30 μM); compounds were tested up to 10 μMand <50% degradation was seen at all concentrations (>10 μM).

TABLE 78 Western Blot Degradation Results. A549 DC₅₀ I -# (μM) I-1   <30I-2   >30 I-3   >30 I-4   >30 I-5   >30 I-6   >30 I-7   <30 I-8   <30I-9   >30 I-10  >30 I-11  >30 I-12  >30 I-13  <30 I-15  >30 I-16  >30I-17  >30 I-21  >30 I-22  >30 I-23  >30 I-26  >10 I-27  >10 I-28  <30I-29  >10 I-30  >10 I-31  >30 I-32  >10 I-33  >10 I-34  <30 I-35  <30I-36  >10 I-37  >10 I-38  >10 I-39  >30 I-43  >30 I-44  >30 I-54  >30I-55  >30 I-58  >30 I-59  >30 I-60  >30 I-61  >30 I-68  >30 I-69  >30I-71  <30 I-80  >30 I-82  >30 I-83  <30 I-84  >30 I-85  <30 I-86  <30I-87  <30 I-88  >30 I-89  <30 I-90  <30 I-91  <30 I-92  >30 I-93  <30I-94  <30 I-95  <30 I-96  >30 I-97  <30 I-99  <30 I-100 <30 I-101 <30I-102 <30 I-103 <30 I-104 <30 I-105 <30 I-106 >30 I-107 <30 I-109 >30I-110 >30 I-111 <30 I-112 <30 I-113 >30 I-114 >30 I-115 <30 I-117 <30I-118 >30

Example 288. HiBiT Assay Protocol

Compound preparation and Cell seeding: The transfected A549 cells wereharvested from dish into cell culture medium and cell numbers counted.Cells were diluted with culture medium to the desired density and 30 μLof cell suspension (about 2000 cells/well) were added into each well ofa 384-well cell culture plate as designated and transferred into 37° C.5% CO₂ incubator for 24 h. Compounds were dissolved to 10 mM stocksolution and 12 μL of the stock solution was transferred to a 384LDV-plate. 3 fold, 10-point dilution was performed by transferring 4 μLcompound into 8 μL DMSO using a TECAN (EVO200) liquid handler. 30 μL ofdiluted compound from compound source plate was transferred into thecell plate as designated by using Echo550 and transferred into 37° C. 5%CO₂ incubator for 24 h.

Detection: Plates were removed from incubators and equilibrated at roomtemperature for 15 minutes. Nano-Glo Hibit Lytic Detection reagent(Promega Cat #N3040) was thawed and equilibrated to room temperaturebefore the experiment. 30 μL of Nano-Glo Hibit Lytic Detection reagentwas added into each well to be detected. The plates were held at roomtemperature for 10 min followed by reading on EnSpire.

Data analysis: The remaining activity was calculated following theformula: Remaining Activity(%)=100%×(Lumsample−LumNC)/(LumPC−LumNC).Calculate the IC₅₀ by fitting the curve using Xlfit (v5.3.1.3), equation201: fit=(A+((B−A)/(1+((x/C){circumflex over ( )}D)))); A: Bottom; B:Top; C: IC₅₀; and D: Slope.

STAT3 HiBiT degradation results for compounds of the invention arepresented in Table 79. The letter codes for STAT3 DC₅₀ include: A (<0.01μM), B (0.01-0.1 μM), C (0.1-1.0 μM), and D (>1.0 μM).

TABLE 79 STAT3 HiBiT Degradation Results STAT3 HiBiT A549 degradation 24h: Average external- I-# Abs DC50 (μM) I-119 D I-120 D I-121 D I-122 DI-123 D I-124 D I-125 C I-126 D I-127 C I-128 C I-129 C I-130 D I-131 DI-132 C I-133 C I-134 D I-135 C I-136 D I-137 B I-138 D I-139 D I-140 DI-141 B I-142 D I-143 D I-144 D I-145 D I-146 C I-147 D I-148 D I-149 DI-150 D I-151 C I-152 D I-153 D I-154 D I-155 D I-156 C I-157 C I-158 DI-159 C I-160 D I-161 D I-162 D I-163 D I-164 B I-165 C I-166 B I-167 CI-168 D I-169 C I-170 D I-171 C I-172 D I-173 D I-174 B I-175 C I-176 DI-177 C I-178 D I-179 C I-180 D I-181 D I-182 C I-183 C I-184 C I-194 BI-195 B I-196 B I-197 C I-198 C I-199 B I-200 D I-202 B I-203 B I-204 BI-205 B I-206 B I-207 C I-208 C I-209 B I-210 D I-211 B I-212 B I-213 AI-214 D I-215 B I-216 B I-217 A I-218 A I-219 C I-220 C I-221 B I-222 DI-223 C I-224 D I-225 C I-226 B I-227 C I-228 C I-229 B I-230 D I-231 BI-232 B I-233 A I-234 B I-235 D I-236 C I-237 B I-238 C I-239 A I-240 BI-241 A I-243 A I-244 A I-245 C I-246 B I-247 B I-248 B I-249 B I-250 BI-251 A I-252 A I-253 A I-254 C I-255 D I-256 D I-257 B I-258 A I-259 CI-260 D I-261 A I-262 A I-263 A I-264 B I-265 B I-266 A I-267 A I-268 CI-269 D I-270 C I-271 C I-272 A I-273 C I-274 C I-275 A I-276 A I-277 BI-278 C I-279 A I-280 B I-281 A I-283 B I-284 B I-285 B I-286 B I-287 DI-288 B I-289 A I-290 A I-292 A I-293 B I-294 A I-295 A

Example 289. Fluorescence Polarization Assays

FIG. 1 . shows that I-1 binds to both STAT3 and E3 ligase.

Example 290. AlphaLISA Assays

FIG. 2 shows that I-1 promotes the formation of the STAT3-degrader-E3ligase ternary complex and STAT3 ubiquitination.

Example 291. Live Cell Degradation Kinetics

TABLE 80 Live Cell Degradation Materials Reagent Vendor Catalog # FuGENEHD Transfection Promega E2311 Reagent (1 mL) 384 well plate, white, flatbottom Grenier Bio-One 781080 Endurazine (1 mL) Promega N2571

700,000 A549 HiBiT cells were seeded in 60 mm dish and rested overnightat 37° C. Cells were transfected with LgBiT vector comprising 6.5 μgplasmid DNA+19.5 μL FuGENE HD transfection reagent per 60 mm dish (scaleup/down as necessary). Following 24 h post transfection, cells weretrypsinized and seeded at 2,000 cells/well in 40 μL in a 384-well plate.Cells were not seeded in the 2 outermost columns/rows to avoidevaporation. Outer wells were filled with PBS. After allowing the cellsto settle overnight, Endurazine 1:100 was added to the cells by firstdiluting 1:10 in media and further diluting 1:10 in 40 μL of cells byadding ˜4.4 μL of diluted Endurazine in plate #1. Cells were incubatedat 37° C. for 2.5 h. Compound was added with Tecan HPd300 dispenser(final DMSO=0.1%) to both plates (10 point, 1:3 dilution; 30 μM topdose). Plate #1 luminescence was read at t=0, 30 min, 1 h, 2 h, 4 h, 6h, 8 h, 16 h, 24 h, 48 h. Plate was returned to incubator between reads.

Part A of FIG. 3 shows that I-103 causes rapid and potent degradation ofSTAT3. FIG. 21 shows that I-174 and I-94 cause rapid and potentdegradation of STAT3.

Example 292. STAT3 MSD Assay Protocol

100 nl of compounds were added into the intermediate plate with Echo(Labcyte 550) from source plate containing a 3-fold serial dilution fromtop concentration of 1 mM. Cells were seeded into 96-well plates (4×104cells/well/100 ul media), mixed well, and incubated for 24 hours. Themedia was aspirated from the cultures and 60 μL pre-chilled PIPA lysisbuffer (Boston BioProducts BP-115D) with protease/phosphatase inhibitor(Roche 05892791001/Roche 04906837001) was added into the well to lyzethe cells for 20 minutes at 4° C. The MSD plate (L15XA) was coated with2 ug/ml capture antibody (ab119352) in PBS and incubated at 4° C.overnight. The next day, the plate was washed three times with TBST (CST#9997S), 150 μL/well. MSD plates were blocked with 150 μL blockingbuffer per well and shaken for 1 hr at RT and 600 rpm. The blockingbuffer was 3% Blocker A (MSD, R93BA-4) in TBST. The MSD plate was washedthree times with 150 μL/well of TBST and 70 μL cell lysate was addedinto the well and shaken for 1 hour at RT and 600 rpm. The MSD plate waswashed three times with 150 μL/well of TBST and added 25 μL/well ofdetection antibody (ab68153) to a final concentration of 1 μg/ml dilutedin 1% blocking buffer and shaken for 1 hour at RT and 600 rpm. MSD platewas washed three times with 150 μL/well of TBST and added 25 μL/well ofSULFO-TAG anti-rabbit antibody (MSD, R32AB-1) to a final concentrationof 1 μg/mL diluted in 1% blocking buffer and shaken for 1 hour at RT and600 rpm. The MSD plate washed three times with 150 μL/well of TBST andadded 150 μL/well of 2×MSD reading buffer diluted from 4×(MSD, R₉₂TC-2)with water. Lastly the MSD instrument was read.

Part B of FIGS. 3 and 5 shows the MSD assay dose-response curve and DC₅₀of I-103 on MOLM-16 (DC₅₀=4 nM) and SU-HDL-1 cells (DC₅₀=28 nM). FIG. 9shows that I-111 degrades mutant STAT3 heme cell lines (DC₅₀=68 nM).FIG. 11 shows that I-83 degrades mutant STAT3 HEK293 cell lines. FIG. 12shows that I-83 degrades mutant STAT3 heme cell lines. FIG. 14 shows theMSD assay dose-response curves of I-174 and I-94 in multiple ALK+ALCLcell lines.

STAT3 MSD DC₅₀ results (μM, % A_(max), 24 hr) in various ALK+ALCL celllines are presented in Table 81 below.

TABLE 81 MSD DC₅₀ Results in ALK+ ALCL Cell Lines I-# SU-DHL-1 SUP-M2KI-JK DEL KARPAS-299 SR-786 1-94 0.015 (>95) 0.062 (95) 0.039 (95) 0.028(97) 0.013 (99) 0.009 (99) 1-174 0.015 (>95) 0.086 (95) 0.047 (97) 0.016(95) ND ND

Example 293. STAT3 RT-qPCR Assay Protocol

SU-DHL-1 cells were treated with compounds for a designed time. 0.3-0.6mL lysis buffer with 2-mercaptoehanol was added to the collected cellpellet or monolayer cells. The cells were vortexed until the cell wasdispersed and the cells appear lysed. One volume of 70% ethanol wasadded to each volume of cell homogenate and vortex. 700 μL of the samplewas transferred to the spin cartridge and centrifuged at 12000 g for 15sat RT. The flow-through was discarded and the process repeated until theentire samples had been processed. 700 ul wash buffer I was added to thespin cartridge and centrifuged at 12000 g for 15s at RT and theflow-through was discarded. 500 μL wash buffer II with ethanol was addedto the spin cartridge and centrifuged at 12000 g for 15s at RT and theflow-through was discarded. The process was then repeated. The spincartridge was centrifuged at 12000 g for 2 min to dry the membrane withbound RNA. 30-100 μL RNase-free water was added to the center of thespin cartridge and incubated for 1 min at RT. The spin cartridge wascentrifuged at 12000 g for 2 min to elute the RNA from the membrane intothe recovery tube and the purified RNA was stored. The concentration ofthe RNA was quantitated using Nano-Drop. cDNA was formed from the RNA byreverse transcription and qPCR of the cDNA with primer of the gene ofinterest and housekeeping gene was preformed using the volumes below:

RNA to cDNA: 2× RT Buffer Mix 10 μL 20× RT Enzyme Mix  1 μL RNA  2 μgTotal volume To 20 μL

qPCR: 2 ×TaqMan  ®Universal PCR Master Mix  5 μL 20 × GADPH(ACTB) TaqManprobe/primer  1 μL cDNA template  1 μL Nuclease free water  3 μL Totalvolume 10 μL

Part A of FIG. 5 shows that 1-103 downregulates STAT3-dependent geneexpression of STAT3, SOCS3, and PDL-1. FIG. 15 shows that I-174 and I-94downregulates STAT3-dependent gene expression of STAT3, SOCS3, andPDL-1.

STAT3 gene expression inhibition results are presented in Table 82below.

TABLE 82 STAT3 Gene Expression Inhibition Results mRNA (RT-qPCR) IC₅₀(μM), 24 hr I-# SOCS3 PD-L1 I-94 0.066 0.030 I-174 0.022 0.029

Example 294. Cell Viability Protocol

Compound-mediated viability effect on MOLM-16 and SU-HDL-1 cells wasquantitatively determined using the CellTiter-Glo® Luminescent CellViability Assay kit from Promega (Catalog number G7572) followingmanufacturer's recommended procedures.

Day 0: 60 nL of compounds/DMSO were stamped to the cell plate as on therecommended platemap. Compound precipitation was observed. Cells werecentrifuged at 800 rpm for 5 min, suspended with culture medium, andcounted with Countess (Invitrogen). The cell density was adjusted to therecommend concentration. 30 μL of cell solution (2000 cells/well) wasadded to the assay plate according to the platemap. 30 μL of media wasadded to column 2 and column 23 as on the platemap. The finalconcentration of the compounds except for the reference compoundPaclitaxel was from 10M, 3-fold dilution and 11 dose (Paclitaxel startedat 500 nM). The final DMSO concentration was 0.2%. The assay plate wasincubated at 37° C., 5% CO₂ for 4 days.

Day 4: The assay plate was equilibrated to RT for ˜10 minutes. Compoundprecipitation was observed (96 h). To determine cell viability, 30 μL ofCellTiter Glo reagent was added to each well and the assay plate wascentrifuged at 1000 rpm for 30 second, incubated at room temperature for10 min, and analyzed by detecting the luminescence using a multimodeplate reader (EnVision 2105, PerkinElmer). The data was then analyzed bysoftware Prism 7.0 from GraphPad and the dose response curves were fitusing a three-parameter logistic equation to calculate EC₅₀.

Part B of FIG. 5 shows that I-103 inhibits MOLM-16 and SU-DHL-1 cellproliferation. FIG. 16 shows that I-174 and I-94 inhibit SU-DHL-1,SUP-M2, KI-JK, DEL, and KARPAS-299 cell proliferation.

Growth inhibition results in various cell lines is provided in Table 83below.

TABLE 83 Cell Viability Results in Various Cell Lines CTG, IC₅₀ μM I-#Cell line Tumor type (% Max inh), Day 4 I-94 SU-DHL-1 ALCL (ALK+) 0.321(89) I-94 SUP-M2 ALCL (ALK+) 0.125 (>95) I-94 KI-JK ALCL (ALK+) 0.102(110) I-94 DEL ALCL (ALK+) 0.038 (>95) I-94 KARPAS-299 ALCL (ALK+) 0.047(85) I-94 SR-786 ALCL (ALK+) 0.25 (85) I-103 SUP-M2 ALCL (ALK+) 0.61(>95) I-103 DEL ALCL (ALK+) 0.11 (>95) I-103 KARPAS-299 ALCL (ALK+) 0.14(50-55) I-103 SR-786 ALCL (ALK+) 3.8 (75) I-111 A3/KAW DLBCL 1.9 (50-55)I-174 SU-DHL-1 ALCL (ALK+) 0.015 (>95) I-174 SUP-M2 ALCL (ALK+) 0.086(95) I-174 KI-JK ALCL (ALK+) 0.047 (97) I-174 DEL ALCL (ALK+) 0.016 (95)I-174 KARPAS-299 ALCL (ALK+) 0.084 (90)

Example 295. Protocol for the Examination of the Effect of Compounds onCell Proliferation, Cell Cycle, Apoptosis and Cell Death in SU-DHL-1Cells

I-103 was evaluated to determine its effect on viability, cell cycle,cell proliferation, apoptosis, and STAT-3 expression. SU-DHL-1 cellswere cultured until sufficient cell numbers were obtained. Timepointswere staggered in order to harvest all cells simultaneously. On day 1,cells were seeded at 12,000 cells per well in five identical 96well-plates. Test compounds at 5 μM, 0.5 μM, and 0.05 μM and controlswere added to the wells designated for the 96-hour timepoint. Testcompound addition was repeated on days 2-4 for the 72, 48, and 24-hourtimepoints.

At day 5, the cells were evaluated for each of the five readouts listedabove. Cell viability was determined by preferentially staining deadcells with 3 μM DAPI. Cell proliferation was measured by Ki-67expression of fixed and permeabilized cells using theFoxp3/Transcription Factor Staining Buffer Set. Cell cycle analysis wasperformed with the PI/RNase Staining Solution on ethanol-fixed cells.Caspase-3 and PARP internal staining was used to determine the level ofapoptosis. STAT-3 expression levels were determined with as describedbelow, fixing cells with 1.60 PFA7 and permeabilizing with methanol inorder to stain cells with a STAT-3 antibody. All plates were analyzed byflow cytometry.

Definitions: non-TC Non-Tissue Culture Treated DPBS Dulbecco’sPhosphate-buffered Saline PFA Paraformaldehyde BSA Bovine Serum AlbuminFBS Fetal Bovine Serum PARP Poly (ADP-ribose) polymerase PEPhycoerythrin

Table 84 shows the reagents used in the protocol.

TABLE 84 Reagents Reagent Vendor Cat. No. Lot no. DPBS HycloneSH30028.02 AE288871274 DAPI Biolegend 422801 B259697 Absolute ethanolFisher BP2818-500 174903 FXCycle PI/RNase kit ThermoFisher F107972091866 BD Stain Buffer BSA BD 554657 9092855 AF647 cleaved PARP BD558710 9070703 PE Active Caspase-3 BD 550914 9073513 (fix/perm); FoxP3internal eBioscience 00-5523-00 2115573 Ki67-APC, 100 tests BioLegend350514 B258553 FBS Peak Serum PS-500A 031C141 100% Methanol FisherA452-4 190931 CST Mouse anti-stat3 CST 9139S 12 PE Goat Anti-MouseBiolegend 405307 B288930 RPMI 1640 Gibco A10491-01 2120437 96-well plateFalcon 351177 9091006 10% BSA Miltenyi 130-091-376 5170608271 Rabbita-Caspase-3 BD 51-68655X 8235860 PFA, 4% in PBS Alfa Aesar J61899Q15F500

Method:

Cell culture: SU-DHL-1 cells were cultured according to DSMZrecommendations for culture medium, passage frequency, and seedingdensity. Briefly, cells were seeded at 0.3×10⁶ cells/mL and passagedevery 2-3 days, not to exceed a cell density of 1.5×10⁶/mL. SU-DHL-1cells were cultured in RPMI 1640 medium supplemented with per FBS.

Co-culture cells and test compounds: SU-DHL-1 cells were harvested andthe concentration was adjusted to 6.67×0 cells/mL. Cells were added tothe wells according to the plate map below (FIG. 1 ). Each well received180 p of cells for a total of 12,000 cells/well, as determined by anoptimal seeding density pilot peformed prior to the initiation of thisexperiment.

A 20 mM DMSO stock solution of I-103 was prepared. I-103 was firstprepared at 1000× in DMSO and then further diluted to 10× in RPMIsupplemented with 10% HI-FBS. I-103 was added at a volume of 20 μL tothe appropriate wells according to the plate maps. Controls wereprepared as described in the table below (Table 85). Drug addition ondays 2-4 followed the same protocol.

TABLE 85 Preparation of Test Compounds and Controls 1000X Prepared inDMSO 10X Prepared in RPMI + 10% HI-FBS Volume needed per Final 1X 1000xcompound per Drug Drug concentration per Conc. Conc. 10X Drug Conc.timepoint = 200 μL    5 μM    5 mM 3 μL 20 mM stock +  50 μM 3 μL 5 mMstock + 9 μl DMSO 297 μL media  0.5 μM  0.5 mM 5 μL 5 mM stock +   5 μM5 μL 0.5 mM stock + 45 μl DMSO 495 μL media 0.05 μM 0.05 mM 5 μL 0.5 mMstock + 0.5 μM 5 μL 0.01 mM stock + 45 μl DMSO 495 μL media Paclitaxel:  25 nM   25 μM 2 μL 10 mM stock + 2.5 μM 20 μL 1000X stock + 798 μlDMSO 1.980 μL media DMSO: 1% DMSO Ctrl 5 μL DMSO + 495 μL stock (0.1%media DMSO final conc)

Evaluation of cells after culture with test compounds: At the conclusionof the 96-hour incubation, each plate was evaluated for one specificendpoint readout.

Readout 1: Viability

The viability plate was removed from the incubator, centrifuged andwashed with 200 μL of DPBS. Cells were centrifuged and the supernatantwas decanted. The cell pellet was resuspended in 120 μL of 3 μM DAPIsolution. Cells were incubated for 10 minutes at room temperature,protected from light. After the incubation, cells were centrifugedagain, decanted and resuspended in 120 μL of BD stain buffer andanalyzed by flow cytometry to determine cell viability.

Readout 2: Cell Cycle

The PI/RNase plate was removed from the incubator, centrifuged andwashed with 200 μL of DPBS. Cells were centrifuged and the supernatantwas decanted. The cell pellet was resuspended in 60 μL of DPBS. Absoluteethanol was added at 140 μL per well and mixed well to fix cells. Cellswere incubated for 10 minutes at 4° C. After the incubation, cells werecentrifuged and washed twice with DPBS. Cells were resuspended in 100 μLof FXCycle PI/RNase and incubated for 25 minutes at room temperature,protected from light. Cells were analyzed by flow cytometry withoutwashing.

Readout 3: Proliferation

The Ki-67 plate was removed from the incubator, centrifuged and washedwith 200 μL of DPBS. Cells were centrifuged and the supernatant wasdecanted. The cell pellet was resuspended in 200 μL of FoxP3 Fix/PermBuffer. Cells were incubated for 30 minutes at room temperature,protected from light. After the incubation, cells were washed twice with1×Perm Buffer. Following the final wash, cells were resuspended in 200μL of BD stain buffer and stored at 4° C. until analysis by flowcytometry. At that time, cells were centrifuged and resuspended in 200μL of 1×Perm Buffer. Again, cells were centrifuged, then resuspended indiluted Ki-67 antibody and incubated for 1 hour at room temperature,protected from light. Subsequent to the incubation with Ki-67 antibody,the volume of each well was brought to 200 μL with 1×Perm Buffer. Cellswere centrifuged to remove unbound antibody. The plate was then washedwith 1×Perm Buffer. After the final centrifugation, 1×Perm Buffer wasdecanted and cells were resuspended in 120 μL BD Stain Buffer andanalyzed by flow cytometry.

Readout 4: Apoptosis

The Caspase-3/PARP plate was removed from the incubator, centrifuged andwashed with 200 μL of cold DPBS. The supernatant was decanted and thecell pellet was resuspended in 100 μL of BD Cytofix/Cytoperm solution.Cells were incubated on ice for 20 minutes, protected from light.Following the incubation, cells were washed twice with BD Perm/WashBuffer. Following the final wash, cells were resuspended in 200 μL of BDstain buffer and stored at 4° C. until analysis by flow cytometry. Atthat time, cells were centrifuged and washed with 200 μL of 1×BDPerm/Wash Buffer. After centrifugation, supernatant was decanted andcells were resuspended in 60 μL of diluted Caspase-3 and PARP antibodycocktail. The plate was incubated for 30 minutes at room temperature,protected from light. Following the antibody incubation, the volume ofeach well was brought to 200 μL with 1×BD Perm/Wash Buffer. Cells werecentrifuged to remove unbound antibody. The plate was then washed with1×BD Perm/Wash Buffer. After the final centrifugation, 1×BD Perm/WashBuffer was decanted and cells were resuspended in 120 μL BD Stain Bufferand analyzed by flow cytometry.

Readout 5: STAT-3 Expression

The STAT-3 plate was removed from the incubator, centrifuged andresuspended in 200 μL of 1.6% PFA. Cells were incubated at roomtemperature for 10 minutes, protected from light. Following theincubation, cells were centrifuged and washed twice with 0.5% BSA inDPBS. Following the final wash, supernatant was decanted and the cellspellets were frozen at −80° until analysis by flow cytometry. At thattime, cells were thawed at room temperature and washed with 0.5% BSA inDPBS. After centrifugation, supernatant was decanted and cells werepermeabilized with 100 μL of 100% cold methanol. The plate was incubatedfor 10 minutes at 4° C., protected from light. Following the antibodyincubation, the plate was washed three times with 0.5% BSA in DPBS.After the final centrifugation, the supernatant was decanted and cellswere resuspended in 50 μL of diluted STAT-3 primary antibody andincubated at room temperature for 1 hour, protected from light.Following the primary antibody incubation, cells were washed twice with0.5% BSA in DPBS. Cells were then stained with a PE-goat anti-mouse IgGsecondary antibody for one hour at room temperature, protected fromlight. Following the incubation with the secondary antibody, cells werewashed three times with 0.5% BSA in DPBS and then resuspended in 120 μLBD 0.5% BSA in DPBS and analyzed by flow cytometry.

Results:

Results are depicted in FIG. 7 . FIG. 7A depicts the decrease of STAT3at 24 hours. FIG. 7B depicts the time-dependent inhibition ofproliferation with I-103. I-103 treatment induces apoptosis at 48 hoursthat leads to cell death as depicted in FIG. 7C and FIG. 7D. FIG. 7Cdepicts the increase in activated Caspase 3 with treatment with I-103.FIG. 7D depicts the increase in subG1 cells (PI/RNAse analysis, FACS)seen at 48, 72, and 96 hours.

Example 296. Caspase Activity Assay

Determination of apoptosis was determined using a Caspase 3/7-Glo assay.

Method Summary

-   -   1- Prepare the Caspase-Glo® 3/7 Reagent (Promega cat #G8090)        -   Equilibrate the Caspase-Glo® 3/7 Buffer and lyophilized            Caspase-Glo® 3/7 Substrate to room temperature before use.        -   Transfer the contents of the Caspase-Glo® 3/7 Buffer bottle            into the amber bottle containing Caspase-Glo® 3/7 Substrate.        -   Mix by swirling or inverting the contents until the            substrate is thoroughly dissolved to form the Caspase-Glo®            3/7 Reagent        -   Aliquot and store at ˜20    -   2- If thawing the reagent, allow it to equilibrate to room        temperature. Mix well.    -   3- Remove white-walled 384-well plate containing treated cells        from the incubator and allow plates to equilibrate to room        temperature.    -   4- Add Caspase-Glo® 3/7 Reagent to each well of the plate at 1:1        ratio with media. Because of the sensitivity of this assay, be        careful not to touch pipet tips to the wells containing samples        to avoid cross-contamination. Cover the plate with a plate        sealer or lid.    -   5- Gently mix contents of wells using a plate shaker at 300-500        rpm for 30 seconds. Incubate at room temperature for 30-60        minutes. Note: Temperature fluctuations will affect the        luminescence reading.    -   6- Measure the luminescence of each sample in a plate-reading        luminometer as directed by the luminometer manufacturer.

STAT3 levels, Caspase activity, and growth inhibition in SU-DHL-1 cellsis shown in FIG. 8 and Table 86. FIG. 17 shows that a decrease of STAT3by 90% using I-174 and I-94 is necessary to induce SU-DHL-1 apoptosisand inhibit cell growth.

TABLE 86 SU-DHL-1 STAT3 levels, apoptosis, and growth inhibition resultsfor I-103 Assay SU-DHL-1 STAT3 levels, MSD DC₉₀ (μM) at 24 hr 0.15Apoptosis, Caspase3/7-Glo IC₅₀ (μM) at 48 hr 0.38 Growth inhibition, CTGIC₅₀ (μM) at 96 hr 0.167

Example 297. Wash-Out Study in SU-DHL-1 Cells

I-103 and I-174 were tested in the wash-out protocol.

Compound wash-out protocol

Day −2 and −1

-   -   Seed cell suspension in T75 flasks and treat with 0.10% DMSO and        1 uM compound for 24 and 48 hr.

Day 0

-   -   Collect cell suspension from the flasks in conical tubes after        24 and 48 hr, spin down at 1,000 rpm for 5 min.    -   Remove supernatant. Wash with PBS, spin down at 1,000 rpm for 5        min, repeat PBS wash one more time.    -   Seed the cells at 2,000 cells per well in 384-well plates for        growth inhibition measurement via CellTiterGlo (CTG) and 10,000        cells per well in 96-well plates for STAT3 levels via MSD.    -   Measure TO for CTG and collect pellets to measure levels of        STAT3 by MSD

Day 1-4

-   -   Measure CTG every day for 4 days post wash-out.    -   Collect pellets and measure levels of STAT3 by MSD every day for        4 days post wash-out. Growth inhibition was normalized to T0 and        graphed as % control.

FIGS. 10 and 18 depict the results of the wash-out studies. FIG. 10Adepicts wash-out results after a 24 hour treatment with I-103. FIG. 10Bdepicts wash-out results after a 48 hour treatment with I-103. FIG. 18depicts the results with I-174 after 24 and 48 hours wash-out. Sustaineddegradation of STAT3 leads to profound effects on the viability ofSU-DHL-1 cells.

Example 298. Deep Tandem Mass Tag Proteomics Protocol

Total protein was isolated from cells (e.g., Molm-16 and SU-DHL-1) andtreated with degrader for 8 hours. Vehicle (DMSO)-treated cells wereused as controls. Protein lysates, 2 biological replicates percondition, were prepared at 4 C in 8M urea, 75 mM NaCl, 1 mM EDTA in 50mM Tris HCl (pH 8), 10 mM NaF, phosphatase inhibitor cocktail 2 (1:100;Sigma, P5726) and cocktail 3 (1:100; Sigma, P0044), 2 μg/mL aprotinin(Sigma, A6103), 10 μg/mL Leupeptin (Roche, 11017101001), and 1 mM PMSF(Sigma, 78830). Lysates were spun at 20,000 rcf for 10 min andsupernatant (containing extracted proteins) was transferred to a cleanmicrocentrifuge tube. Protein concentrations were determined using thePierce BCA assay. Protein lysates were reduced with 5 mM dithiothreitol(Thermo Scientific, 20291) for 45 min at room temperature and alkylatedwith 10 mM iodoacetamide (Sigma, A3221) for an additional 45 min.Protein digests were diluted 1:4 with 50 mM Tris HCl (pH 8) beforedigestion with LysC (Wako, 100369-826) for 2 h and with trypsin(Promega, V511X) overnight. Both lysis steps were performed at a 1:50enzyme-to-protein ratio and at room temperature. Digested samples wereacidified with formic acid (FA; Fluka, 56302) to a final concentrationof 1% (final pH of <3), and then centrifuged at 2,000 rcf for 5 min toclear precipitated urea. Peptide lysates were desalted on C18 SepPakcolumns (Waters, 100 mg/1 cc) and dried down using a SpeedVacConcentrator (Savant SC210A). Desalted peptides were then labeled withtandem mass tag (TMT, Thermo Fisher Scientific) reagents according tothe manufacturer's instructions. TMT labeling was quenched andTMT11-plex was combined, desalted on a C18 SepPak column (Waters, 500mg/6 cc) and fractionated by high-pH reversed phase off-linechromatography into 24 fractions. Briefly, desalted TMT labelledpeptides were loaded on a 4.6 mm×250 mm column RP Zorbax 300A Extend-C18column (Agilent, 3.5 μm bead size), and separated on an Agilent 1100Series HPLC instrument using basic reversed-phase chromatography.Ninety-six fractions were collected and subsequently concatenated asdescribed earlier into 24 fractions. Each fraction was dried down andresuspended in 3% MeCN/0.1% FA to a peptide concentration of 1 μg/μL forLC-MS/MS analyses of the proteome. Online fractionation was performedusing a nanoflow Proxeon EASY-nLC 1200 UHPLC system (Thermo FisherScientific) and separated peptides were analyzed on a benchtop OrbitrapQ Exactive plus mass spectrometer (Thermo Fisher Scientific). All datawere analyzed using Spectrum Mill software package (AgilentTechnologies). Identities interpreted for individual spectra wereautomatically designated as confidently assigned using the Spectrum Millautovalidation module to use target-decoy based false discovery rate(FDR) estimates to apply score threshold at the spectral and proteinlevels. In total, 10,992 proteins were quantified. Downstreambioinformatic analysis was performed in Perseus software (developed byMax Planck Institute of Biochemistry, Munich, Germany).

Degradation in Molm-16 and SU-DHL-1 cells was highly selective for STAT3vs >10,000 other detected proteins (including all other STAT familymembers) as evaluated by deep tandem mass tag proteomics. FIGS. 4 and 13show proteomic scatterplots for I-103 and I-174 respectively.

Example 299. Xenograph Tumor Studies

Animals: 50 6-8 week old female NOD SCID mice weighing 18 to 20 grams.25 mice were used in each study.

Quarantine: Animals were quarantined for 7 days before study. Thegeneral health of the animals was evaluated by a veterinarian, andcomplete health checks were performed. Animals with abnormalities wereexcluded prior the study.

Housing: General procedures for animal care and housing were inaccordance with the standard, Commission on Life sciences, NationalResearch Council, Standard operating procedures (SOPs) of Pharmaron,Inc. The mice were kept in laminar flow rooms at constant temperatureand humidity with 3-5 mice in each cage. Animals were housed inpolycarbonate cages (300×180×150 mm³) in an environmentally monitored,well-ventilated room maintained at a temperature of (22±3° C.) and arelative humidity of 40% 80%. Fluorescent lighting provided illuminationapproximately 12 hours per day. The bedding material was soft wood,which was changed once per week.

Animal ID: Each animal was assigned an identification number; thefollowing identification method was applied. Each cage card was labeledwith such information as study number, group, sex, dose, animal number,initiation date, study director and telephone number. Individual animalswere identified by ear coding.

Diet: Animals had free access to irradiation sterilized dry granule foodduring the entire study period except for time periods specified by theprotocol. Sterile drinking water in a bottle was available to allanimals ad libitum during the quarantine and study periods. The bottleand the stopper with attached sipper tube was autoclaved prior to use.Samples of water from the animal facility were analyzed and results ofwater analysis will be retained in the facility records and werereviewed by the veterinarian, or designee, to assure that no knowncontaminants are present that could interfere with or affect the outcomeof studies.

Method for Tumor Inoculation: Each mouse was inoculated subcutaneouslywith SU-DHL-1 tumor cells (1×107+Matrigel) or SUP-M2 tumor cells(5×106+Matrigel) in 0.1 ml of RPM11640 medium supplemented with 10% FBS,100 U/ml penicillin and 100 mg/ml streptomycin for tumor development.Mice were then assigned to groups such that the mean tumor volume wasthe same for each treatment group and time point. The treatments wereadministered to the tumor-bearing mice accordingly to the study designshowed in Table 87 (SU-DHL1) and Table 88 (SUP-M2). Vehicle was 25%HP-β-CD in water adjusted to pH 7.4.

TABLE 87 Groups and Treatments (SU-DUL-1) Dose Group Animals/ DoseVolume # Group Drug (mg/kg) (mL/kg) Route Regimen 1 5 Vehicle — 5 IP 2days on/5 days off × 2 wks 2 5 1-174 2.5 5 IP 2 days on/5 days off × 2wks 3 5 1-174 5 5 IP 2 days on/5 days off × 2 wks 4 5 1-174 10 5 IP 2days on/5 days off × 2 wks 5 5 1-174 25 5 IP 2 days on/5 days off × 2wks

TABLE 88 Groups and Treatments (SUP-M2) Dose Group Animals/ Dose Volume# Group Drug (mg/kg) (mL/kg) Route Regimen 1 5 Vehicle — 5 IV 2 dayson/5 days off × 2 wks 2 5 1-174 3 5 IV 2 days on/5 days off × 2 wks 3 51-174 10 5 IV 2 days on/5 days off × 2 wks 4 5 1-174 30 5 IV 2 days on/5days off × 2 wks 5 5 1-174 30 5 IV QW × 2 wks

Measurement Parameters: Study animals were monitored not only for tumorgrowth but also behavior such as mobility, food and water consumption(by cage side checking only), body weight (BW), eye/hair matting and anyother abnormal effect. Any mortality and/or abnormal clinical signs wasrecorded. Sponsor was notified immediately if abnormal clinical signs,or if tolerability issues were observed. Body weights of all animalswere measured and recorded twice per week. The measurement of tumor sizewas conducted twice weekly with a caliper and recorded. The tumor volume(mm3) was estimated using the formula: TV=a×b2/2, where “a” and “b” arelong and short diameters of a tumor, respectively. 100012341 Results:FIG. 19 shows that intermittent dosing of A-174 achieves tumorregression in ALK+ALCL xenograph model SU-DHL-1. FIG. 20 shows thatintermittent dosing of 1-174 achieves tumor regression in ALK+ALCLxenograph model SUP-M2.

Results for additional compounds of the invention in SUDHL-1 xenographtumor studies according to the above protocol are shown in Table 89.Letter codes for tumor volume include A<500 mm³, B=500-1000 mm³, C=>1000mm³.

TABLE 89 2.5-30 mg/kg and 2 days on/5 days off Compound Route 5 days 10days 15 days 20 days Vehicle IV B B C C I-94 IV A B C C I-103 IP A A A AI-174 IV A A A A I-174 IP A A A A I-195 IP A A A A I-196 IP A A A AI-233 IV A A A A I-241 IV A A A A I-261 IP A A A A I-262 IV A A A AI-275 IP A A A A

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1-25. (canceled)
 26. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 29. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 30. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 31. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 33. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 34. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 35. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 36. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 37. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 38. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 39. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 40. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 41. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 42. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 43. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 44. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 45. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 46. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 47. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 48. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 49. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 50. The compound of claim26, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 51. A pharmaceuticalcomposition comprising a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 52. The pharmaceuticalcomposition of claim 51, wherein said compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 53. The pharmaceuticalcomposition of claim 51, wherein said compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 54. The pharmaceuticalcomposition of claim 51, wherein said compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 55. The pharmaceuticalcomposition of claim 51, wherein said compound is selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.